HK1145180A - Heteroaryl amides useful as inhibitors of voltage-gated sodium channels - Google Patents

Description

Heteroaryl amides as inhibitors of voltage-gated sodium channels

Technical Field

The present invention relates to compounds useful as inhibitors of voltage-gated sodium channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

Background

Na channels are the center of action potential production by all excitable cells (e.g. neurons and muscle cells). They play an important role in excitable tissues, including the brain, gastrointestinal smooth muscle, skeletal muscle, peripheral nervous system, spinal cord and airways. They therefore play an important role in a variety of disease states, such as epilepsy (a)See alsoBertrand (2002) "Epilepsy and sodium channels"Expert Opin.Ther. Patents 12(1)：85-91)), pain (See alsoWaxman, S.G., S.Dib-Hajj et al, (1999) "Sodium channels and pain"Proc Natl Acad Sci U SA96(14): 7635-9 and Waxman, S.G., T.R.Cummins et al, (2000) "Voltage-gated sodium channels and the molecular pathophylo f pain: a review "J Rehabil Res Dev37(5): 517-28), muscular rigidity (Ginseng radix (Panax ginseng C.A. Meyer) In the light of the above, see,Meola，G.and V.Sansone(2000)“Therapy in myotonicdisorders and in muscle channelopathies”Neurol Sci21(5): s953-61 and Mankodi, A. and C.A.Thornton (2002) "Myotonics syntromes"Curr Opin Neurol15(5): 545-52), ataxia (ataxia)Referring to the description of the preferred embodiment,meisler, M.H., J.A. Kearney et al, (2002) "variants of voltage-controlled sodium channels in motion disorders and conditions"Novartis Found Symp241: 72-81), multiple sclerosis (Referring to the description of the preferred embodiment,black, J.A., S.Dib-Hajj et al, (2000) "sensor nerve-specific channel SNS is innominated in the bridges of microorganisms exogenous bacterial infection and humans with multiple strains"Proc Natl Acad Sci USA97(21): 11598- "Brain Res959(2): 235-42), irritable bowel syndrome (I), (II)Referring to the description of the preferred embodiment,su, X., R.E.Wa chtel et al, (1999) "Capsaicin sensing and voltage-gated sodium currents in colon sensing sources from front root of mouth"Am J Physiol277(6Pt 1): g1180-8, and Laird, J.M., V.Souslova et al, (2002) "Deficitsinvirscarpain and referred hyperthermagesia in Nav1.8(SNS/PN3) -null mice"J Neurosci22(19): 8352-6), urinary incontinence and visceral pain (C: (A)Referring to the description of the preferred embodiment,yoshimura, N.S.seki et al, (2001) "The innovative of The tetrodotoxin-resistant sodium channel Na (v)1.8(PN3/SNS) in arat model of visceral pain"J Neurosci21(21): 8690-6), and a series of psychiatric dysfunctions, such as anxiety anddepression (A)Referring to the description of the preferred embodiment,Hurley，S.C.(2002)“Lamotrigine update and its use in mood disorders”Ann Pharmacother 36(5)：860-73)。

voltage-gated Na channels comprise a gene family consisting of 9 different subtypes (nav1.1-nav 1.9). As shown in Table 1, these subtypes show tissue-specific localization and functional differences: (Referring to the description of the preferred embodiment,Goldin，A.L.(2001)“Resurgence of sodiumchannel research”Annu Rev Physiol63: 871-94). Three members of this gene family (nav1.8, 1.9, 1.5) are resistant to blockade by the well-known Na channel blocker TTX, demonstrating subtype specificity within this gene family. Mutational analysis has identified glutamate 387 as a key residue for TTX binding ((ii))Referring to the description of the preferred embodiment,noda, M.H.Suzuki et al, (1989) "A single point interaction controls tetrodotoxin and savoxin sensitivity on the sodium channel II"FEBS Lett 259(1)：213-6)。

Table 1 (abbreviations: CNS ═ central nervous system, PNS ═ peripheral nervous system, DRG ═ dorsal root ganglion, TG ═ trigeminal ganglion):

na isoforms	Tissue of	TTX IC50	Indications of
				NaV1.1	Soma of CNS, PNS neurons	10nM	Pain, epilepsy, neurodegeneration
NaV1.2	CNS, high in axons	10nM	Neurodegeneration and epilepsy
				NaV1.3	CNS, embryonic, damaged nerves	15nM	Pain (due to cold or dampness)
NaV1.4	Skeletal muscle	25nM	Myotonia
				NaV1.5	Heart and heart	2μM	Arrhythmia, Long QT
NaV1.6	Distributed throughout the CNS, most abundant	6nM	Pain, movement disorder
				NaV1.7	PNS, DRG, neuroendocrine Ends	25nM	Pain, neuroendocrine disorders
NaV1.8	PNS，DRG&Small neurons in TG	＞50μM	Pain (due to cold or dampness)
				NaV1.9	PNS，DRG&Small neurons in TG	1μM	Pain (due to cold or dampness)

In general, voltage-gated sodium channels (navs) are responsible for triggering rapid elevation of action potentials in excitable tissues of the nervous system, which transmit electrical signals that program and encode normal and abnormal pain sensations. Antagonists of NaV channels can attenuate these pain signals and are useful in the treatment of a variety of pain conditions including, but not limited to, acute, chronic, inflammatory and neuropathic pain. Known NaV antagonists, e.g. TTX, lidocaine: (Referring to the description of the preferred embodiment,Mao，J.and L.L.Chen(2000)“Systemic lidocaine for neuropathic pain relief”Pain87(1): 7-17), bupivacaine, phenytoin (b)Referring to the description of the preferred embodiment,Jensen，T.S.(2002)“Anticonvulsants in neuropathic pain：rationale and clinicalevidence”Eur J Pain6(Suppl A): 61-8), lamotrigine (Referring to the description of the preferred embodiment,Rozen，T.D.(2001)“Antiepileptic drugs in the management of clusterheada che and trigeminal neuralgia”Headache41 Suppl 1: s25-32 and Jensen, T.S. (2002) "Antimon vulsants in neuropathic pain: rational and clinical evidence "Eur J Pain6(Suppl A): 61-8) and carbamazepine (Referring to the description of the preferred embodiment,Backonja，M.M.(2002)“Use of anticonvulsantsfor treatment of neuropathic pain”Neurology59(5Suppl 2): s14-7), have been shown to be useful for alleviating pain in human and animal models.

Pain that develops in the presence of tissue damage or inflammationHyperalgesia (hypersensitivity to certain pains) reflects, at least in part, an increase in excitability of the high-threshold primary afferent neurons that innervate the site of injury. Voltage sensitive sodium channel activation is crucial for the generation and propagation of neuronal action potentials. There is increasing evidence that regulation of NaV current is an endogenous mechanism for controlling neuronal excitability (ii) ((iii))Referring to the description of the preferred embodiment,Goldin，A.L.(2001)“Resurgenceof sodium channel research”Annu Rev Physiol63: 871-94). Several kinetically and pharmacologically distinct voltage-gated sodium channels are found in Dorsal Root Ganglion (DRG) neurons. TTX-tolerance currents are insensitive to micromolar concentrations of tetrodotoxin and exhibit slow activation and inactivation kinetics and a more depolarizing activation threshold compared to other voltage-gated sodium channels. TTX-tolerant sodium currents are mainly limited to a subset of sensory neurons that may be involved in nociception. Specifically, TTX-tolerant sodium currents are expressed almost exclusively in neurons with small cell body diameters; causing small diameter, slow-conducting axons and responding to capsaicin. A large body of experimental evidence demonstrates that TTX-resistant sodium channels are expressed on C-fibers and play an important role in the transmission of nociceptive information to the spinal cord.

Intrathecal administration of antisense oligo-deoxynucleotides targeted to unique regions of TTX-resistant sodium channels (NaV1.8) results in PGE₂A significant reduction in the hyperalgesia induced (Referring to the description of the preferred embodiment,khasar, S.G., M.S.gold et al, (1998) "Atetrodotoxin-resistant sodium current reagents in a membrane in the rat"Neurosci Lett256(1): 17-20). Recently, Wood and colleagues have developed a knockout mouse strain that lacks functional NaV1.8. In an assay to assess the response of animals to the inflammatory agent carrageenan, the mutation has an analgesic effect: (See alsoAkopian, A.N., V.Souslova et al, (1999) "The tetrodotoxin-resistant sodium channel SNS has associated function in pain ways"Nat Neurosci2(6): 541-8). In addition, defects in mechanical and temperature perception were observed in these animals. Analgesia exhibited by NaV1.8 knockout mutants and related to TTX-toleranceThe observation of the role of the receptor current in nociception is consistent.

Immunohistochemistry, in situ hybridization, and in vitro electrophysiology all showed that sodium channel nav1.8 selectively localizes to small sensory neurons of the dorsal root ganglion and trigeminal ganglion: (Referring to the description of the preferred embodiment,akopion, A.N., L.Sivilotti et al, (1996) "Atetrodotoxin-resistant voltage-gated sodium channel expressed by sensory nerves"Nature379(6562): 257-62). The primary role of these neurons is the detection and transmission of noxious stimuli. Antisense and immunohistochemical evidence also supported the role of nav1.8 in neuropathic pain: (Referring to the description of the preferred embodiment,lai, J., M.S. gold et al, (2002) "Inhibition of neuropathic pain by depletion expression of the tetrodotoxin-resistant sodium channel, NaV1.8"Pain95(1-2): 143-52, and Lai, J., J.C. Hunter et al, (2000) "Block of neuropathic pad by antisense targetinggof tetrodotoxin-resistant sodium channels"Methods Enzymol314: 201-13). The nav1.8 protein is up-regulated along intact C-fibers adjacent to nerve damage. Antisense therapy can prevent redistribution of nav1.8 along the nerve, reversing neuropathic pain. The combination of gene-knockout and antisense data supports the role of nav1.8 in the detection and transmission of inflammatory and neuropathic pain.

In neuropathic pain states, there is a modification of Na channel distribution and subtype. In damaged nerves, expression of NaV1.8 and NaV1.9 is greatly reduced, while expression of TTX-sensitive subunit NaV1.3 is up-regulated by 5-10 fold ((S))Referring to the description of the preferred embodiment,Dib-Hajj, S.D., J.Fjell et al, (1999) "plastics of sodium channel expression in DRGneturs in the cyclic compliance in j."Pain83(3): 591-600). In animal models following nerve injury, the time course of increased nav1.3 parallels the appearance of allodynia. The biophysical peculiarity of the nav1.3 channel is that it shows a very fast reactivation following the inactivation of the action potential. Generates a sustained heightRate of firing, which is often seen in damaged nerves (Referring to the description of the preferred embodiment,cummins, t.r., f.aglieco et al, (2001) "nav 1.3 sodium channels: rapid reprinting and slow closed-state activation display expression in a macromolecular cell and in a molecular sensor nerves "J Neurosci21(16): 5952-61). Nav1.3 is expressed in the central and peripheral systems of humans. NaV1.9 is similar to NaV1.8 in that it also selectively concentrates on small sensory neurons in the dorsal root ganglia and trigeminal ganglia: (Referring to the description of the preferred embodiment,fang, x., l.djouhri et al, (2002). "The present and roll soft-resistive sodium channel Na (v)1.9(NaN) innovative primary sources neurones"J Neurosci22(17): 7425-33). It has a slow rate of inactivation and a voltage dependence that shifts to the left with respect to activation: (Ginseng radix (Panax ginseng C.A. Meyer) In the light of the above, see,Dib-Hajj, S., J.A.Black et al, (2002) "NaN/Nav1.9: a Sodiumchannels with unique properties "Trends Neurosci25(5): 253-9). These two biophysical properties allow nav1.9 to play a role in establishing the resting membrane potential of nociceptive neurons. The resting membrane potential of cells expressing NaV1.9 was in the range of-55 to-50 mV, compared to-65 mV for most other peripheral and central neurons. This persistent depolarization is largely due to the persistently low levels of nav1.9 channel activation. This depolarization makes it easier for the neuron to reach a threshold at which an action potential is evoked in response to a nociceptive stimulus. Compounds that block the nav1.9 channel may play an important role in determining the set point for the detection of pain stimuli. In chronic pain states, nerves and nerve endings can become swollen and allergic, showing a high frequency of action potentials with mild or even no stimulation. These pathological neural swellings are called neuromas, where the major Na channels expressed are nav1.8 and nav1.7 (a)Referring to the description of the preferred embodiment,kretschmer, T, L.T.Happel et al, (2002) "Accumulation of PN1 and PN3 sodium channels in painfu humaneuroma-evidence from immunocytochemistry"Acta Neurochir(Wien)144(8): 803-10; dispatch 810). NaV1.6 and NaV1.7Is also expressed in dorsal root ganglion neurons and has an effect on the small TTX-sensitive components found in these cells. Thus, in addition to its role in neuroendocrine excitability, nav1.7 may be a potential pain target in particular: (Referring to the description of the preferred embodiment,klugbauer, N.N., L.Lacinova et al, (1995) "Structure and functional expression of a new member of the tetrodotoxin-induced acoustic channel family from human neuroendocrine cells"Embo J 14(6)：1084-90)。

NaV1.1(Referring to the description of the preferred embodiment,sugawara, T.T., E.Mazaki-Miyazaki et al, (2001) "Nav1.1 variants of house nonwoven partitions associated with partial partitions.Neurology57(4): 703-5) and NaV1.2(Ginseng radix (Panax ginseng C.A. Meyer) In the light of the above, see,sugawa ra, T., Y.Tsurubuchi et al, (2001) "Amissense mutitiono f the Na + channel alpha II subBunnit gene Na (v)1.2 in a antibiotic with a felt and an afebrile peptides uses channels dye function"Proc Natl Acad Sci USA98(11): 6384-9) are associated with epileptic disorders including febrile seizures. More than 9 genetic mutations in NaV1.1 are associated with febrile seizures (Referring to the description of the preferred embodiment,meisler, M.H., J.A. Kearney et al, (2002) "mutagenesis of vol-gated sodium channels in motion disorders and peptides"Novartis Found Symp 241：72-81)。

Antagonists of nav1.5 have been developed for the treatment of cardiac arrhythmias. A genetic defect in NaV1.5 that produces a larger, current-inactive component is associated with the long QT in humans, and an orally available local anesthetic, mexiletine, has been used to treat this disease (Referring to the description of the preferred embodiment,wang, D.W., K.Yazawa et al, (1997) "Pharmacological targeting of Long QT mutans channels"J Clin Invest 99(7)：1714-20)。

Several Na channel blockers are currently used or clinically tried for the treatment of epilepsy (Ginseng radix (Panax ginseng C.A. Meyer) In the light of the above, see,mounrd, B, and D.Bertrand (2002) "Epilepsy and sodium channels"Expert Opin.Ther.Patents 12(1): 85-91); acute pain (Referring to the description of the preferred embodiment,wiffen, P., S.Collins et al, (2000) "anticancer drug for access and respiratory pain"Cochrane Database Syst Rev3) Chronic pain (1)Referring to the description of the preferred embodiment,wiffen, P., S.Collins et al, (2000) "anticancer drugs for access and respiratory pain"Cochrane Database Syst Rev3, and Guay, D.R, (2001) "joining agents of viral pain"Pharmacotherapy21(9): 1070-81), inflammatory pain (Referring to the description of the preferred embodiment,Gold，M.S.(1999)“Tetrodotoxin-resistant Na+currents and inflammatory hyperalgesia.”Proc Natl Acad Sci USA96(14): 7645-9), and neuropathic pain (c)Referring to the description of the preferred embodiment,strichartz, G.R., Z.Zhou et al, (2002) "therapeutic concentrations of local and inflammatory uneils of sodium channels in neuropathic pain"Novartis Found Symp241: 189-201, and Sandner-Kiesling, A., G.Rumpold Seitlinger et al, (2002) "Lamotrigine monootherpy for control of neural after-market section"Acta Anaesthesiol Scand46(10): 1261-4); arrhythmia (A)Referring to the description of the preferred embodiment,an, R.H., R.Bangalore et al, (1996) "Lidocaine Block of LQT-3 mutant human Na + channels"Circ Res79(1): 103-8, and Wang, D.W., K.Yazawa et al, (1997) "pharmaceutical targeting Long QT mutant gases"J Clin Invest99(7): 1714-20); neuroprotection (A)Referring to the description of the preferred embodiment,Taylor，C.P.and L.S.Narasimhan(1997)“Sodiumchannels and therapy of central nervous system diseases”Adv Pharmacol39: 47-98) and use as anesthetic(s)Referring to the description of the preferred embodiment,strichartz, G.R., Z.Zhou et al, (2002) "Therapeutic concentrations of localized admixture of inorganic salts of inorganic channels of inorganic salts.Novartis Found Symp 241：189-201)。

Various animal models of clinical significance have been developed for studying sodium channel modulators for a variety of different pain indications. For example, malignant chronic pain (see, Kohase, H. et al, Acta Anaesthesil Scand.2004; 48 (3): 382-3); femoral cancer pain (see, Kohase, H. et al, Acta Anaesthesiol Scand.2004; 48 (3): 382-3); non-malignant chronic bone pain (see, Ciocon, J.O. et al, JAm GeriaatrSoc.1994; 42 (6): 593-6); rheumatoid arthritis (see Calvino, B. et al, Behav Brain Res.1987; 24 (1): 11-29); osteoarthritis (see, Guzman, R.E., et al, Toxicol Pathol.2003; 31 (6): 619-24); spinal stenosis (see, Takenobu, Y. et al, J Neurosci methods.2001; 104 (2): 191-8); neuropathic low back Pain (see, Hines, R. et al, Pain Med. 2002; 3 (4): 361-5; Massie, J.B. et al, J Neurosci methods.2004; 137 (2): 283-9);

neuropathic low back Pain (see, Hines, R. et al, Pain Med. 2002; 3 (4): 361-5; Massie, J.B. et al, J Neurosci methods.2004; 137 (2): 283-9); myofascial Pain syndrome (see, Dalpiaz & Dodds, J Pain Palliat CarePharmacother.2002; 16 (1): 99-104; Sluka KA et al, Muscle nerve.2001; 24 (1): 37-46); fibromyalgia (see Bennet & Tai, Int J Clin Pharmacol Res.1995; 15 (3): 115-9); temporomandibular joint pain (see Ime H, Ren K, Brain Res Mol Brain Res.1999; 67 (1): 87-97); chronic visceral pain, including abdominal pain (see Al-Chaer, e.d. et Al, gastroenterology.2000; 119 (5): 1276-85); pelvic/perineal pain (see Wesselmann et al, Neurosci Lett.1998; 246 (2): 73-6); pancreatic pain (see Vera-Portocarro, L.B. et al, anesthesiology.2003; 98 (2): 474-84);

IBS pain (see Verne, G.N. et al, pain. 2003; 105 (1-2): 223-30; La JH et al, World gastroenterol.2003; 9 (12): 2791-5); chronic headache (see, Willimas & Stark, Cephalalgia.2003; 23 (10): 963-71); migraine (see Yamamura, H. et al, J neurophysiol.1999; 81 (2): 479-93); tension headaches, including cluster headaches (see Costa, A. et al, cephalalgia.2000; 20 (2): 85-91); chronic neuropathic Pain, including post-herpetic neuralgia (see, Attal, N. et al, neurology.2004; 62 (2): 218-25; Kim & Chung 1992, Pain 50: 355); diabetic neuropathy (see, Beidouna et al, Clin J pain.2004; 20 (3): 174-8; Courteix, C. et al, pain.1993; 53 (1): 81-8); HIV-associated neuropathy (see, Portegies & Rosenberg, New Tijdschr Genesekd.2001; 145 (15): 731-5; Josepheik et al, pain.2004; 107 (1-2): 147-58; Oh, S.B. et al, J Neurosci.2001; 21 (14): 5027-35); trigeminal neuralgia (see, Sato, J. et al, Oral surgor Med Oral saline Oral radial end.2004; 97 (1): 18-22; Imamura Y et al, Exp Brain Res.1997; 116 (1): 97-103);

Charcot-Marie Tooth neuropathy (see, Sereda, M. et al, neuron. 1996; 16 (5): 1049-60); hereditary sensory neuropathy (see, Lee, M.J. et al, Hum Mol Genet.2003; 12 (15): 1917-25); peripheral nerve damage (see, Attal, N. et al, neurology.2004; 62 (2): 218-25; Kim & Chung 1992, Pain 50: 355; Bennett & Xie, 1988, Pain 33: 87; Decoded, I. & Woolf, C.J., 2000, Pain 87: 149; Shir, Y. & Seltzer, Z.1990; Neurosci Lett 115: 62); painful neuroma (see, Nahabenian & Johnson, Ann plant Surg.2001; 46 (1): 15-22; Devor & Raber, Behavv Neural biol.1983; 37 (2): 276-83); ectopic proximal and distal discharges (see Liu, X. et al, Brain Res.2001; 900 (1): 119-27); radiculopathy (see Devers & Galer, (see Clin J pain.2000; 16 (3): 205-8; Hayashi N et al, spine.1998; 23 (8): 877-85); chemotherapy-induced neuropathic pain (see, Aley, K.O. et al, neuroscience.1996; 73 (1): 259-65); radiation therapy-induced neuropathic pain;

post-mastectomy pain (see, Devers & Galer, Clin J pain.2000; 16 (3): 205-8); central pain (Cahana, a. et al, Anesth analg.2004; 98 (6): 1581-4), spinal cord injury pain (see, Hains, b.c. et al, Exp neurol.2000; 164 (2): 426-37); pain following stroke; thalalgia (see, LaBuda, C.J. et al, Neurosci Lett.2000; 290 (1): 79-83); complex regional pain syndrome (see, Wallace, M.S. et al, anesthesiology.2000; 92 (1): 75-83; Xantos D et al, J pain.2004; 5(3 Suppl 2): S1); phantom pain (see, Weber, W.E., Ned Tijdschr Genesekd.2001; 145 (17): 813-7; Levitt & Heyback, pain.1981; 10 (1): 67-73); intractable pain (see Yokoyama, M. et al, Can J Anaesth.2002; 49 (8): 810-3); acute pain, acute post-operative pain (see, Koppert, W. et al, Anesth Analg.2004; 98 (4): 1050-5; Brennan, T.J. et al, pain. 1996; 64 (3): 493 501); acute musculoskeletal pain; arthralgia (see, Gotoh, S. et al, Ann Rheum Dis.1993; 52 (11): 817-22); mechanical low back pain (see, Kehl, L.J. et al, pain.2000; 85 (3): 333-43); neck pain; tendonitis; injury/athletic pain (see, Sesay, M. et al, Can J Anaesth.2002; 49 (2): 137-43); acute visceral pain, including abdominal pain; pyelonephritis; appendicitis; cholecystitis (cholecystitis); ileus; hernia, etc. (see, Giambernadrino, M.A. et al, pain.1995; 61 (3): 459-69); chest pain, including cardiac pain (see, Vergona, R.A. et al, Life Sci.1984; 35 (18): 1877-84); pelvic pain, renal colic, acute obstetric pain, including childbirth pain (see, Segal, S. et al, Anesth Analg.1998; 87 (4): 864-9); cesarean pain; acute inflammatory pain, burn pain, and wound pain; acute intermittent pain, including endometriosis (see, Cason, A.M. et al, Horm Behav.2003; 44 (2): 123-31);

acute herpes zoster pain; sickle cell anemia; acute pancreatitis (see, Toma, H; gastroenterology.2000; 119 (5): 1373-81); breakthrough pain; orofacial pain, including sinusitis pain, dental pain (see, Nusstein, J. et al, J Endo.1998; 24 (7): 487-91; Chidiac, J.J. et al, Eur J pain.2002; 6 (1): 55-67); multiple Sclerosis (MS) pain (see, Sakurai & Kanazawa, J neurol Sci.1999; 162 (2): 162-8); pain in depression (see Greene B, CurrMed Res Opin.2003; 19 (4): 272-7); leprosy pain; becker's disease pain; painful obesity (see Devilers & Oranje, Clin Exp Dermatol.1999; 24 (3): 240-1); venous inflammatory pain; Guillain-Barre disease (Guillain-Barre) pain; lower limb pain and toe movement; haglund syndrome; erythromelalgia (see, Legroux-Crespel, E. et al, Ann Dermatol Venoreol. 2003; 130 (4): 429-33); fabry disease pain (see, German, D.P., J Soc biol. 2002; 196 (2): 183-90); bladder and genitourinary disorders including urinary incontinence (see, Berggren, t. et al, J urol.1993; 150(5 Pt 1): 1540-3); overactive bladder (see Chuang, Y.C. et al, urology.2003; 61 (3): 664-70); painful bladder syndrome (see, Yoshimura, N. et al, J Neurosci.2001; 21 (21): 8690-6); interstitial Cystitis (IC) (see, Giannakopoulos & Campilomotors, Arch Ital Urol Newrol Androl.1992; 64 (4): 337-9; Boucher, M. et al, J Urol.2000; 164 (1): 203-8); and prostatitis (see Mayersak, J.S., Int Surg.1998; 83 (4): 347-9; Keith, I.M. et al, J Urol.2001; 166 (1): 323-8).

Unfortunately, as noted above, the efficacy of sodium channel blockers currently used in the above disease states is largely limited by a number of side effects. These side effects include various CNS disorders such as blurred vision, dizziness, nausea and sedation, as well as more potentially life-threatening arrhythmias and heart failure. Such undesirable side effects can be avoided by using Na channel blockers that exhibit a degree of selectivity in their anti-Na channel subtype activity. However, the Na channel blockers currently on the market lack this selectivity. Perhaps because of the lack of molecular selectivity, drugs currently on the market exhibit drug-dependent blockade and often exhibit higher affinity at depolarizing potentials, leading to preferential targeting of actively discharged neurons, which is considered to be a key factor in the therapeutic window of existing Na channel-blocking drugs. Despite each drug's own unique therapeutic profile, current Na channel blockers are often associated with Central Nervous System (CNS) and Cardiovascular (CV) side effects, including bloodPressure changes, which side effects often limit the dosage. Dizziness, sedation, nausea, ataxia and confusion of consciousness are caused by the use of phenytoin^TMMexiletine^TMAnd lidocaine^TMSome specific adverse reactions were observed.

Thus, there remains a need to develop other Na channel antagonists, preferably those with higher potency and fewer side effects.

Disclosure of Invention

It has now been found that the compounds of the present invention and pharmaceutically acceptable compositions thereof are useful as inhibitors of voltage-gated sodium channels. These compounds are of the general formula I:

or a pharmaceutically acceptable derivative thereof.

These compounds and pharmaceutically acceptable compositions may be used to treat or reduce the severity of a variety of diseases, disorders or conditions, including, but not limited to, acute, chronic, neuropathic or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, neuralgia in general, epilepsy or epilepsy disorders, neurodegenerative diseases, psychiatric disorders such as anxiety and depression, bipolar disorders, muscular rigidity, cardiac arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritic pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, penetrating pain, post-operative pain, cancer pain, stroke, cerebral ischemia, neuropathic pain, cardiac pain, traumatic brain injury, amyotrophic lateral sclerosis, stress-or exercise-induced angina, palpitation, hypertension, migraine or abnormal gastrointestinal activity.

Detailed Description

Definitions and general terms

The present invention relates to compounds of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

ring B is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein ring B is optionally substituted with up to x R³Substitution;

X¹、X²、X³and X⁴Each independently is nitrogen or C-R⁴Provided that X is¹、X²、X³And X⁴Is not nitrogen at the same time;

R^Aselected from SO₂N(R²)₂、SO₂R¹、NR²SO₂R¹；

R¹Is C_1-6Aliphatic radical in which up to 2 atoms other than the atom bound to the nitrogen or oxygen atom are optionally O, S, NR^NOr C (O) instead;

each R²Independently hydrogen, or C_1-6Aliphatic radical in which up to 2 carbon atoms, other than the atom bound to the nitrogen atom, are optionally O, S, NR^NOr C (O) instead;

x is 0 to 4;

R^Neach independently selected from hydrogen or C_1-6An aliphatic group optionally substituted with 1-3 independent substituents selected from the group consisting of: -R^JOxo, thio, -CO₂R^J、-OR^J、-N(R^J)₂、-SR^J、-NO₂Halogen, -CN, -C_1-4Haloalkyl, -C_1-4Haloalkoxy, -C (O) N (R)^J)₂、-NR^JC(O)R^J、-SO₂R^J、-SO₂N(R^J)₂、-NR^JSO₂R^J、-NR^JCON(R^J)₂、-NR^JCO₂R^J、-COR^J、-OCOR^J、-OCON(R^J)₂、-SOR^J、-NR^JSO₂N(R^J)₂、-COCOR^J、-COCH₂COR^J、-OP(O)(OR^J)₂、-P(O)(OR^J)₂、-PO(OR^J)(R^J)、-P(O)(R^J)₂or-OP (O) (R)^J)₂(ii) a Wherein

R^JIs hydrogen or unsubstituted C_1-6An aliphatic group;

R³and R⁴Each independently is Q-R^X；

Q is a bond or C_1-6An aliphatic chain in which up to 3 methylene units of Q are optionally and independently replaced by: -NH-, -NR-, -O-, -S-, -CO-, -C₂-、-OC(O)-、-C(O)CO-、-C(O)-、-C(S)-、-C(O)NH-、-C(O)NR-、-C(＝N-CN)-、-NHCO-、-NRCO-、-NHC(O)O-、-NRC(O)O-、-SO₂NH-、-SO₂NR-、-NHSO₂-、-NRSO₂-、-NHC(O)NH-、-NRC(O)NH-、-NHC(O)NR-、-NRC(O)NR、-OC(O)NH-、-OC(O)NR-、-NHSO₂NH-、-NRSO₂NH-、-NHSO₂NR-、-NRSO₂NR-, -SO-or-SO₂-; wherein

Q is optionally substituted with 1-3 independent R^QAnd (3) substitution:

R^Xeach independently selected from-R', halogen, -NO₂、-CN、-OR′、-SR′、-N(R′)₂、-NR′C(O)R′、-NR′C(O)N(R′)₂、-NR′CO₂R′、-C(O)R′、-CO₂R′、-OC(O)R′、-C(O)N(R′)₂、-OC(O)N(R′)₂、-SOR′、-SO₂R′、-SO₂N(R′)₂、-NR′SO₂R′、-NR′SO₂N(R′)₂、-C(O)C(O)R′、-C(O)CH₂C(O)R′、-OP(O)(OR′)₂、-P(O)(OR′)₂、-PO(OR′)(R′)、-P(O)(R′)₂or-OP (O) (R')₂；

Each R is independently selected from hydrogen or C_1-6An aliphatic group optionally substituted with 1-3 independent substituents selected from the group consisting of: -R^T、-T-Ar¹Halogen, oxo, thio, -OR^T、-SR^T、-N(R^T)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R^T、-COR^T、-CON(R^T)₂、-OCOR^T、-NR^TCOR^T、-SO₂R^T、-SO₂N(R^T)₂or-NR^TSO₂R^T(ii) a Wherein

Each R^TIndependently is hydrogen or unsubstituted C_1-6An aliphatic group; or

Any two R on the same substituent or different substituents^TThe groups together with the atoms to which each group is attached optionally form a 3-8 membered saturated or partially unsaturated monocyclic, or 5-6 membered monocyclic aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein said monocyclic ring is optionally substituted with 1-3 independent substituents selected from the group consisting of: -R^R、-T-Ar¹Halogen, oxo, thio, -OR^R、-SR^R、-N(R^R)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R^R、-COR^R、-CON(R^R)₂、-OCOR^R、-NR^RCOR^R、-SO₂R^R、-SO₂N(R^R)₂or-NR^RSO₂R^R(ii) a Wherein

Each R^RIndependently is hydrogen or unsubstituted C_1-6An aliphatic group;

t is (CH)₂)_w；

w is 0 to 2;

Ar¹selected from a 3-8 membered saturated or partially unsaturated ring, a 5-6 membered aromatic ring, a 3-7 membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein

Ar¹Optionally substituted with 1-3 independent substituents: -R^WOxo, thio, -CO₂R^W、-OR^W、-N(R^W)₂、-SR^W、-NO₂Halogen, -CN, -C_1-4Haloalkyl, -C_1-4Haloalkoxy, -C (O) N (R)^W)₂、-NR^WC(O)R^W、-SO₂R^W、-SO₂N(R^W)₂、-NR^WSO₂R^W、-NR^WCON(R^W)₂、-NR^WCO₂R^W、-COR^W、-OCOR^W、-OCON(R^W)₂、-SOR^W、-NR^WSO₂N(R^W)₂、-COCOR^W、-COCH₂COR^W、-OP(O)(OR^W)₂、-P(O)(OR^W)₂、-PO(OR^W)(R^W)、-P(O)(R^W)₂or-OP (O) (R)^W)₂(ii) a Wherein

R^WIs hydrogen or unsubstituted C_1-6An aliphatic group;

R^Qselected from halogen, -R^S、-N(R^S)₂、-SR^S、-OR^S、C_3-10Alicyclic group, C_6-10Aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, oxo, thioxo, -C_1-4Haloalkoxy, -C_1-4Haloalkyl, -NO₂、-CN、-CF₃、-OCF₃、-CO₂R^S、-COR^S、-OC(O)R^Sor-NR^SC(O)R^S(ii) a Wherein

R^SIs hydrogen or unsubstituted C_1-6An aliphatic group; or

Any two R on the same substituent or different substituents^QOr two R^SA group, or R^QGroup and R^SAny combination of groups, together with one or more atoms to which each group is attached, optionally form a 3-8 membered saturated or partially unsaturated monocyclic, or 5-6 membered monocyclic aromatic ring; each ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein any of said monocyclic rings is optionally substituted with 1-3 independent substituents selected from the group consisting of: r⁰Halogen, oxo, thio, -OR⁰、-SR⁰、-N(R⁰)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R⁰、-COR⁰、-CON(R⁰)₂、-OCOR⁰、-NR⁰COR⁰、-SO₂R⁰、-SO₂N(R⁰)₂or-NR⁰SO₂R⁰(ii) a Wherein

R⁰Is hydrogen or unsubstituted C_1-6An aliphatic group;

r' is independently selected from hydrogen or C_1-8Aliphatic radical, C_6-10Aryl, heteroaryl ring having 5-10 ring atoms, or heterocyclic ring having 3-10 ring atoms, or wherein R and R 'together with the atom or atoms to which they are attached, or 2R' together with the atoms to which they are attached, form a 5-8 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein said C_1-8Aliphatic radical, C_6-10The aryl, heteroaryl ring or heterocycle is optionally substituted with 1-3 independent substituents selected from the group consisting of: r^IHalogen, oxo, thio, -OR^I、-SR^I、-N(R^I)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R^I、-COR^I、-CONHR^I、-OCOR^I、-NR^ICOR^I、-SO₂R^I、-SO₂N(R^I)₂or-NR^ISO₂R^I(ii) a Wherein

R^IIs hydrogen or unsubstituted C_1-6An aliphatic group.

The compounds of the present invention include those generally described above, and are further illustrated by the classes, subclasses, and specific compounds disclosed herein. The following definitions as used herein should be used unless otherwise indicated. For the purposes of the present invention, the identification of chemical elements is carried out according to the periodic Table of the elements, CAS edition, Handbook of Chemistry and Physics, 75 th edition. In addition, the general principles of Organic Chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999 and "March's Advanced Organic Chemistry", 5 th edition, eds: smith, m.b. and March, j., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

As described herein, the compounds of the invention may be optionally substituted with one or more substituents as generally described above, or as exemplified for particular classes, subclasses, and particular compounds of the invention. It is to be understood that the phrase "optionally substituted" may be used interchangeably with the phrase "substituted or unsubstituted. In general, the term "(substituted)" whether preceded by the term "optionally" or not, indicates that a hydrogen atom in a given structure is replaced with the indicated substituent group. Unless otherwise specified, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents at each position may be the same or different.

As used herein, when the term "optionally substituted" precedes a list of listed items, then the term applies to all of the substitutable groups that follow in the list. For example, if X is halogen, optionally substituted C_1-3Alkyl or phenyl; x may be optionally substituted alkyl or optionally substituted phenyl. Likewise, if the term "optionally substituted" follows the recitation of a list, unless otherwise indicated, the term also applies to all substitutable groups in the list. For example: if X is halogen, C_1-3Alkyl or phenyl, wherein X is optionally J^XSubstituted, then C_1-3Both alkyl and phenyl groups may optionally be substituted by J^XAnd (4) substitution. It will be apparent to one of ordinary skill in the art that groups such as H, halogen, NO₂、CN、NH₂OH or OCF₃Are not included because they are not groups that may be substituted. A substituent group or structure is unsubstituted if it is not identified or defined as "optionally substituted".

Combinations of substituents encompassed by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable" as used herein means a compound that is not substantially altered when subjected to conditions that permit its production, detection, preferably recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound refers to a compound that does not substantially change when held at a temperature of 40 ℃ or less for at least one week in the absence of moisture or other chemically reactive conditions.

The term "aliphatic" or "aliphatic group" as used herein means a straight (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or that contains one or more units of unsaturation. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, while in other embodiments aliphatic groups contain 1-4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups. Further examples of aliphatic groups include, but are not limited to, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or 2-ethylhexyl. The term "alkyl" and the prefix "alk-" as used herein include both straight and branched saturated carbon chains.

The term "alkylene" as used herein refers to a saturated divalent straight or branched chain hydrocarbon group such as methylene, ethylene, isopropyl, and the like. The term "alkylene" as used herein refers to a divalent straight chain alkyl linking group.

The term "alkenyl" as used herein refers to an aliphatic group containing 2 to 8 (e.g., 2 to 6 or 2 to 4) carbon atoms and at least one carbon-carbon double bond. Like the alkyl group, the alkenyl group may be linear or branched. Examples of alkenyl groups include, but are not limited to, allyl, isoprenyl, 2-butenyl, and 2-hexenyl.

The term "alkynyl" as used herein refers to an aliphatic group containing 2 to 8 (e.g., 2 to 6 or 2 to 4) carbon atoms and at least one carbon-carbon triple bond. The alkynyl group may be linear or branched. Examples of alkynyl groups include, but are not limited to, propargyl and butynyl.

The term "cycloaliphatic" (or "carbocycle") as used herein refers to a monocyclic C₃-C₈Hydrocarbons or bicyclic radicals C₈-C₁₂A hydrocarbon, which is fully saturated or contains one or more units of unsaturation, but is not aromatic, having a single point of attachment to the rest of the molecule, wherein any one of the rings of the bicyclic ring system is 3-7 membered. Suitable alicyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Further examples of aliphatic radicals include cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptylAnd cycloheptenyl.

The term "heteroaliphatic" as used herein refers to an aliphatic group in which one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon. Heteroaliphatic groups can be substituted or unsubstituted, straight or branched chain, cyclic or acyclic, and include "heterocyclic", "heterocyclyl", "heteroalicyclic", or "heterocyclic" groups.

The term "heterocycle", "heterocyclyl", "heteroalicyclic" or "heterocyclic" as used herein refers to a non-aromatic, monocyclic, bicyclic or tricyclic ring system in which one or more ring members are independently selected heteroatoms. In some embodiments, the "heterocycle", "heterocyclyl", "heteroalicyclic", or "heterocyclic" group has 3 to 14 ring members, wherein one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3 to 8 ring members.

Examples of heterocycles include, but are not limited to, the following monocyclic rings: tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, tetrahydropyrazin-1-yl, tetrahydropyrazin-2-yl, tetrahydropyrazin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, pyrazolin-1-yl, pyrazolin-3-yl, pyrazolin-4-yl, pyrazolin-2-yl, and the like, Pyrazolin-5-yl, thiazolidin-2-yl, thiazolidin-3-yl, thiazolidin-4-yl, thiazolidin-5-yl, imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, imidazolidin-5-yl; and the following bicyclic rings: 3-1H-benzimidazol-2-one, 3- (1-alkyl) -benzimidazol-2-one, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiophene (benzodithiolane), benzodithiane, and 1, 3-dihydro-imidazol-2-one.

The term "heteroatom" as used herein refers to one or more of oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; any basic nitrogen quaternized form, or(ii) a Heterocyclic substitutable nitrogens, e.g. N (as in 3, 4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺(as in N-substituted pyrrolidinyl).

The term "unsaturated" as used herein refers to a moiety having one or more units of unsaturation.

The term "alkoxy" or "thioalkyl" as used herein, refers to an alkyl group, as defined previously, attached to the bulk carbon chain through an oxygen ("alkoxy") or sulfur ("thioalkyl") atom.

The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" refer to an alkyl, alkenyl or alkoxy group which may be optionally substituted with one or more halogen atoms.

The term "haloaliphatic" refers to an aliphatic group substituted with 1-3 halogens. For example, the term haloalkyl includes the group-CF₃。

The term "halogen" or "halo" as used herein refers to fluorine, chlorine, bromine or iodine.

The term "oxo" as used herein means ═ O.

The term "thio" as used herein means ═ S.

The term "carbonyl" refers to-C (O) -.

The term "aryl" used alone or as part of a larger moiety such as "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to a monocyclic ring (e.g., phenyl); bicyclic (e.g., indenyl, naphthyl, tetrahydronaphthyl, tetrahydroindenyl); and tricyclic (e.g., fluorenyl, tetrahydrofluorenyl, or tetrahydroanthracenyl, anthracenyl) ring systems, wherein a monocyclic ring system is aromatic, or at least one ring in a bicyclic or tricyclic ring system is aromatic, and each ring in the system contains 3-7 ring members. Bicyclic or tricyclic groups include 2-3 membered carbocyclic rings fused to benzene. For example, the groups fused to benzene include groups with 2 or more C_4-8Phenyl fused to a carbocyclic moiety. The term "aryl group"may be used interchangeably with the term" aryl (yl) ring ".

The term "bicyclic system" as used herein includes 8-12 (e.g., 9, 10, or 11) membered structures forming 2 rings, wherein the two rings have at least one atom in common (e.g., 2 atoms in common). Bicyclic systems include bicyclic cycloaliphatic groups (e.g., bicycloalkyl or bicycloalkenyl), bicyclic heteroaliphatic groups, bicyclic aryl groups, and bicyclic heteroaryl groups.

The term "heteroaryl" used alone or as part of a larger moiety such as "heteroaralkyl" or "heteroarylalkoxy" refers to monocyclic, bicyclic, and tricyclic ring systems having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms (e.g., N, O, S, or combinations thereof), and each ring in the system contains 3 to 7 ring members, with only one point of attachment to the rest of the molecule. Heteroaryl includes ring systems having 2 to 3 rings fused to benzene. For example, a benzene-fused group includes a benzene fused to 1 or 2 4-8 membered heteroalicyclic moieties (e.g., indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [ b ] furanyl, benzo [ b ] thienyl, quinolinyl, or isoquinolinyl). The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic".

Without limitation, monocyclic heteroaryl rings include the following groups: furyl (e.g., furan-2-yl or furan-3-yl); imidazolyl (e.g., N-imidazolyl, imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl); isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl); oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, or oxazol-5-yl); pyrrolyl (e.g., N-pyrrolyl, pyrrol-2-yl or pyrrol-3-yl); pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl); pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, or pyrimidin-5-yl); pyridazinyl (e.g., pyridazin-3-yl, pyridazin-4-yl, pyridazin-5-yl or pyridazin-6-yl); thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, or thiazol-5-yl); tetrazolyl (e.g., tetrazol-1-yl or tetrazol-5-yl); triazolyl (e.g., 2-triazolyl or 5-triazolyl); thienyl (e.g., thien-2-yl or thien-3-yl); pyrazolyl (e.g., pyrazol-2-yl, pyrazol-3-yl, or pyrazol-4-yl); an isothiazolyl group; 1, 2, 3-oxadiazolyl; 1, 2, 5-oxadiazolyl; 1, 2, 4-oxadiazolyl; 1, 2, 3-triazolyl; 1, 2, 3-thiadiazolyl; 1, 3, 4-thiadiazolyl; 1, 2, 5-thiadiazolyl; a pyrazinyl group; 1, 3, 5-triazinyl. Monocyclic heteroaryls are numbered according to standard chemical nomenclature.

Without limitation, bicyclic heteroaryl groups include the following groups: indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [ b ] furanyl, benzo [ b ] thienyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, or 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), indolizinyl, isoindolyl, indolyl, benzo [ b ] furanyl, benzo [ b ] thienyl, indazolyl, benzimidazolyl, benzothiazolyl, purinyl, 4H-quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1, 8-naphthyridinyl, or pteridinyl. Bicyclic heteroaryls are numbered according to standard chemical nomenclature.

In some embodiments, an aryl (including aralkyl, aralkoxy, aryloxyalkyl, and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy, and the like) group may contain one or more substituents. Suitable substituents on the unsaturated carbon atom of the aryl or heteroaryl group are selected from the group consisting of³，R⁴，R⁵，R^N，R^J，R^Q，R^XR' or R^WThose listed in the definitions of (1). Other suitable substituents include: halogen; -R^o；-OR^o；-SR^o(ii) a1, 2-methylenedioxy; 1, 2-ethylenedioxy; optionally substituted with R^oSubstituted phenyl (Ph); optionally substituted with R^oSubstituted-o (ph); optionally substituted with R^oSubstituted- (CH)₂)_1-2(Ph); optionally substituted with R^osubstituted-CH ═ CH (ph); -NO₂；-CN；-N(R^o)₂；-NR^oC(O)R^o；-NR^oC(S)R^o；-NR^oC(O)N(R^o)₂；-NR^oC(S)N(R^o)₂；-NR^oCO₂R^o；-NR^oNR^oC(O)R^o；-NR^oNR^oC(O)N(R^o)₂；-NR^oNR^oCO₂R^o；-C(O)C(O)R^o；-C(O)CH₂C(O)R^o；-CO₂R^o；-C(O)R^o；-C(S)R^o；-C(O)N(R^o)₂；-C(S)N(R^o)₂；-OC(O)N(R^o)₂；-OC(O)R^o；-C(O)N(OR^o)R^o；-C(NOR^o)R^o；-S(O)₂R^o；-S(O)₂OR^o；-S(O)₂N(R^o)₂；-S(O)R^o；-NR^oS(O)₂N(R^o)₂；-NR^oS(O)₂R^o；-N(OR^o)R^o；-C(＝NH)-N(R^o)₂；-(CH₂)_0-2NHC(O)R^o；-L-R^o；-L-N(R^o)₂；-L-SR^o；-L-OR^o；-L-(C_3-10Alicyclic group), -L- (C)_6-10Aryl), -L- (5-10 membered heteroaryl), -L- (5-10 membered heterocyclyl), oxo, C_1-4Haloalkoxy, C_1-4Haloalkyl, -L-NO₂、-L-CN、-L-OH、-L-CF₃(ii) a Or two substituents together with the intervening atoms to which they are attached form a 5-7 membered saturated, unsaturated or partially saturated ring, wherein L is C_1-5Alkylene in which up to 3 methylene units are substituted by-NH-, -NR^o-、-O-、-S-、-C(O)O-、-OC(O)-、-C(O)CO-、-C(O)-、-C(O)NH-、-C(O)NR^o-、-C(＝N-CN)、-NHCO-、-NR^oCO-、-NHC(O)O-、-NR^oC(O)O-、-S(O)₂NH-、-S(O)₂NR^o-、-NHS(O)₂-、-NR^oS(O)₂-、-NHC(O)NH-、-NR^oC(O)NH-、-NHC(O)NR^o-、-NR^oC(O)NR^o、-OC(O)NH-、-OC(O)NR^o-、-NHS(O)₂NH-、-NR^oS(O)₂NH-、-NHS(O)₂NR^o-、-NR^oS(O)₂NR^o-, -S (O) -or-S (O)₂-substituted, and wherein each independent R^oSelected from hydrogen, optionally substituted C_1-6Aliphatic, unsubstituted 5-8 membered heteroaryl or heterocycle, phenyl, -O (Ph) or-CH₂(Ph), or, two independent R on the same substituent or different substituents^oAnd each R^oOne or more of the atoms to which the groups are attached together form a 5-8 membered heterocyclyl, aryl or heteroaryl ring or a 3-8 membered cycloalkyl ring, wherein the heteroaryl or heterocyclyl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. R^oThe optional substituents on the aliphatic radical of (A) are selected from NH₂、NH(C_1-4Aliphatic radical), N (C)_1-4Aliphatic radical)₂Halogen, C_1-4Aliphatic radical, OH, O (C)_1-4Aliphatic group), NO₂、CN、CO₂H、CO₂(C_1-4Aliphatic radical), O (halogeno C)_1-4Aliphatic group) or halogeno C_1-4An aliphatic radical, in which R^oEach of the above C_1-4Aliphatic groups are unsubstituted.

In some embodiments, the aliphatic, cycloaliphatic, heteroaliphatic, or non-aromatic heterocycle may contain one or more substituents. In some cases, two substituents on the same atom or on different atoms may, together with the intervening atoms to which they are attached, form a 5-7 membered saturated, unsaturated or partially saturated ring containing 0-3 heteroatoms selected from N, O or S. Suitable substituents on the saturated carbon of the aliphatic or heteroaliphatic or non-aromatic heterocyclic ring are selected from those listed above for the unsaturated carbon of the aryl or heteroaryl group, and in addition include the following groups: o, S, NNHR^*、＝NN(R^*)₂、＝NNHC(O)R^*、＝NNHCO₂(alkyl), ═ NNHS (O)₂(alkyl) or ═ NR^*Wherein each R^*Independently selected from hydrogen or optionally substituted C_1-6Aliphatic radicals, or two R on the same nitrogen^*Together with the nitrogen atom form a 5-8 membered heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfurOr a heteroaromatic ring. R^*The optional substituents on the aliphatic radical of (A) are selected from NH₂、NH(C_1-4Aliphatic radical), N (C)_1-4Aliphatic radical)₂Halogen, C_1-4Aliphatic radical, OH, O (C)_1-4Aliphatic group), NO₂、CN、CO₂H、CO₂(C_1-4Aliphatic radical), O (halogeno C)_1-4Aliphatic group) or halo (C)_1-4Aliphatic radical) in which R^*Each of the above C_1-4Aliphatic groups are unsubstituted.

In some embodiments, the optional substituent on the nitrogen of the non-aromatic heterocycle comprises-R⁺、-N(R⁺)₂、-C(O)R⁺、-C(O)OR⁺、-C(O)C(O)R⁺、-C(O)CH₂C(O)R⁺、-S(O)₂R⁺、-S(O)₂N(R⁺)₂、-C(＝S)N(R⁺)₂、-C(＝NH)-N(R⁺)₂or-NR⁺S(O)₂R⁺(ii) a Wherein R is⁺Is hydrogen, optionally substituted C_1-6Aliphatic group, optionally substituted phenyl group, optionally substituted-O (Ph), optionally substituted-CH₂(Ph), optionally substituted- (CH)₂)_1-2(Ph); optionally substituted-CH ═ CH (ph); or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring having 1-4 heteroatoms independently selected from oxygen, nitrogen or sulfur, or 2 independent R on the same or different substituents⁺And each R⁺One or more atoms to which groups are attached together form a phenyl, 5-8 membered heterocyclyl, 5-8 membered heteroaryl, or 3-8 membered cycloalkyl ring, wherein the heteroaryl or heterocyclyl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. R⁺Is selected from-NH or an optional substituent on the phenyl ring₂、-NH(C_1-4Aliphatic group), -N (C)_1-4Aliphatic radical)₂Halogen, C_1-4Aliphatic radical, -OH, -O (C)_1-4Aliphatic group), -NO₂、-CN、-C(O)OH、-C(O)O(C_1-4Aliphatic group), -O (halo (C)_1-4Aliphatic group)) or halo (C)_1-4Aliphatic radical) in which R⁺Each of the above C_1-4Aliphatic groups are unsubstituted.

As described above, in some embodiments, 2 independent R^o(or R)⁺Or any other variable similarly defined herein) together with one or more atoms to which each variable is attached form a 3-8 membered cycloalkyl, heterocyclyl, aryl or heteroaryl group having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. 2 independent R^o(or R)⁺Or any other similarly defined variable herein) along with the atom to which each variable is attached include, but are not limited to, the following: a)2 independent R^o(or R)⁺Or any other variable similarly defined herein) is attached to the same atom and, together with that atom, forms a ring, e.g., N (R)^o)₂Wherein 2R^oTogether with the nitrogen atom, form piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl; and b)2 independent R^o(or R)⁺OR any other variable similarly defined herein) are attached to different atoms and, together with these two atoms, form a ring, e.g. when the phenyl group is substituted with 2 OR' s^oWhen substitutedThe 2R^oTogether with the oxygen atoms to which they are attached form a fused 6-membered oxygen containing ring:it is understood that 2 independent R^o(or R)⁺Or any other variable similarly defined herein) and the atoms to which each variable is attached may form various other rings, the examples detailed above being non-limiting.

In some embodiments, the methylene unit of the alkyl or aliphatic chain is optionally replaced by another atom or group. Examples of such atoms or groups include, but are not limited to, -NR^o-、-O-、-S-、-C(O)O-、-OC(O)-、-C(O)CO-、-C(O)-、-C(O)NR^o-、-C(＝N-CN)、-NR^oCO-、-NR^oC(O)O-、-S(O)₂NR^o-、-NR^oS(O)₂-、-NR^oC(O)NR^o-、-OC(O)NR^o-、-NR^oS(O)₂NR^o-, -S (O) -or-S (O)₂-, wherein R^oAs defined herein. Unless otherwise indicated, the above alternatives form chemically stable compounds. The substitution of optional atoms or groups may occur within the chain or at either end of the chain; i.e. at the connection points and/or at the ends. The two optional substitutions may also be linked to each other within the chain, provided that it results in a chemically stable compound. Unless otherwise indicated, if a substitution occurs at a terminus, the substituting atom is attached to the terminal H. For example, if-CH₂CH₂CH₃Optionally substituted by-O-, the resulting compound may be-OCH₂CH₃、-CH₂OCH₃or-CH₂CH₂OH。

As described herein, a bond drawn from one substituent to the center of one ring within a polycyclic ring system (as shown below) represents the substitution of that substituent at any substitutable position in any ring within the polycyclic ring system. For example, FIG. a represents a possible substitution at any of the positions shown in FIG. b.

This also applies to polycyclic ring systems fused to optional ring systems (which may be represented by dashed lines). For example, in figure c, X is an optional substituent for ring D and ring E.

However, if two rings in a polycyclic ring system each have a different substituent drawn from the center of each ring, then each substituent represents only the substituent on the ring to which it is attached, unless otherwise specified. For example, in figure D, Y is only an optional substituent for ring D and X is only an optional substituent for ring E.

The term "protecting group" as used herein refers to those groups intended to protect functional groups, such as alcohols, amines, carboxyl groups, carbonyl groups, and the like, from undesirable reactions during synthetic operations. Commonly used protecting Groups are disclosed in Greene and Wuts, Protective Groups in organic Synthesis, 3 rd edition (John Wiley & Sons, New York, 1999), which is incorporated herein by reference. Examples of nitrogen protecting groups include acyl, aroyl or carbamoyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthaloyl, o-nitrophenoxyacetyl, α -chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl and chiral auxiliaries, such as protected or unprotected D, L or D, L-amino acids, for example alanine, leucine, phenylalanine and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3, 4-dimethoxybenzyloxycarbonyl, 3, 5-dimethoxybenzyloxycarbonyl, 2, 4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4, 5-dimethoxybenzyloxycarbonyl, 3, 4, 5-trimethoxybenzyloxycarbonyl, 1- (p-biphenylyl) -1-methylethoxycarbonyl, α -dimethyl-3, 5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butoxycarbonyl, diisopropylmethoxycarbonyl, isopropoxycarbonyl, ethoxycarbonyl, p-chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-nitrobenzyloxy, Methoxycarbonyl, allyloxycarbonyl, 2, 2, 2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like, aralkyl groups such as benzyl, trityl, benzyloxymethyl and the like and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

The term "prodrug" as used herein refers to a compound that is converted in vivo to a compound of any of the formulae listed herein. This conversion can be accomplished, for example, by hydrolysis of the prodrug form in blood or enzymatic conversion to the parent form in blood or tissue. Prodrugs of the compounds of the present invention may be, for example, esters. Esters which may be used as prodrugs in the present invention are phenyl esters, aliphatic radicals (C)₁-C₂₄) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the invention containing an OH group may be acylated at the OH position to form a prodrug form thereof. Other prodrug forms include phosphate esters, for example, those formed by phosphorylation of an OH group on the parent compound. In T.Higuchi and V.Stella, Pro-drugs as novel Delivery Systems, Vol.14 of the A.C.S.Sympossium Series, Edward B.Roche, ed., Bioreproducible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and Judkins et al, Synthetic Communications 26 (23): 4351-4367, 1996, which are each incorporated herein by reference, provides a thorough discussion of prodrugs.

Unless otherwise indicated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational) forms of the structure; for example, the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, single stereochemical isomers as well as mixtures of enantiomers, mixtures of diastereomers and mixtures of geometric isomers (or conformers) of the compounds of the present invention are within the scope of the present invention. All tautomers of the compounds of the invention unless otherwise indicatedAll structural forms are within the scope of the present invention. In addition, unless otherwise indicated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, except for replacement of hydrogen by deuterium or tritium or replacement of carbon by deuterium¹³C-or¹⁴Compounds having the structure of the present invention other than C-enriched carbon substitution are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or sodium channel blockers with improved therapeutic properties.

As used herein¹H NMR stands for proton nuclear magnetic resonance and TLC for thin layer chromatography.

Description of the Compounds of the invention

In one embodiment, the present invention provides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

ring B is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein ring B is optionally substituted with up to x R³Substitution;

X¹、X²、X³and X⁴Each independently is nitrogen or C-R⁴Provided that X is¹、X²、X³And X⁴Is not nitrogen at the same time;

R^Aselected from SO₂N(R²)₂、SO₂R¹、NR²SO₂R¹；

R¹Is C_1-6Aliphatic radical in which up to 2 atoms other than the atom bound to the nitrogen or oxygen atom are optionally O, S, NR^NOr C (O) instead;

each R²Independently hydrogen, or C_1-6Aliphatic radical in which up to 2 carbon atoms, other than the atom bound to the nitrogen atom, are optionally O, S, NR^NOr C (O) instead;

x is 0 to 4;

R^Neach independently selected from hydrogen or C_1-6An aliphatic group optionally substituted with 1-3 independent substituents selected from the group consisting of: -R^JOxo, thio, -CO₂R^J、-OR^J、-N(R^J)₂、-SR^J、-NO₂Halogen, -CN, -C_1-4Haloalkyl, -C_1-4Haloalkoxy, -C (O) N (R)^J)₂、-NR^JC(O)R^J、-SO₂R^J、-SO₂N(R^J)₂、-NR^JSO₂R^J、-NR^JCON(R^J)₂、-NR^JCO₂R^J、-COR^J、-OCOR^J、-OCON(R^J)₂、-SOR^J、-NR^JSO₂N(R^J)₂、-COCOR^J、-COCH₂COR^J、-OP(O)(OR^J)₂、-P(O)(OR^J)₂、-PO(OR^J)(R^J)、-P(O)(R^J)₂or-OP (O) (R)^J)₂(ii) a Wherein

R^JIs hydrogen or unsubstituted C_1-6An aliphatic group;

R³and R⁴Each independently is Q-R^X；

Q is a bond or C_1-6An aliphatic chain in which up to 3 methylene units of Q are optionally and independently replaced by: -NH-, -NR-, -O-, -S-, -CO-, -C₂-、-OC(O)-、-C(O)CO-、-C(O)-、-C(S)-、-C(O)NH-、-C(O)NR-、-C(＝N-CN)-、-NHCO-、-NRCO-、-NHC(O)O-、-NRC(O)O-、-SO₂NH-、-SO₂NR-、-NHSO₂-、-NRSO₂-、-NHC(O)NH-、-NRC(O)NH-、-NHC(O)NR-、-NRC(O)NR、-OC(O)NH-、-OC(O)NR-、-NHSO₂NH-、-NRSO₂NH-、-NHSO₂NR-、-NRSO₂NR-, -SO-or-SO₂-; wherein

Q is optionally substituted with 1-3 independent R^QAnd (3) substitution:

R^Xeach independently selected from-R', halogen, -NO₂、-CN、-OR′、-SR′、-N(R′)₂、-NR′C(O)R′、-NR′C(O)N(R′)₂、-NR′CO₂R′、-C(O)R′、-CO₂R′、-OC(O)R′、-C(O)N(R′)₂、-OC(O)N(R′)₂、-SOR′、-SO₂R′、-SO₂N(R′)₂、-NR′SO₂R′、-NR′SO₂N(R′)₂、-C(O)C(O)R′、-C(O)CH₂C(O)R′、-OP(O)(OR′)₂、-P(O)(OR′)₂、-PO(OR′)(R′)、-P(O)(R′)₂or-OP (O) (R')₂；

Each R is independently selected from hydrogen or C_1-6An aliphatic group optionally substituted with 1-3 independent substituents selected from the group consisting of: -R^T、-T-Ar¹Halogen, oxo, thio, -OR^T、-SR^T、-N(R^T)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R^T、-COR^T、-CON(R^T)₂、-OCOR^T、-NR^TCOR^T、-SO₂R^T、-SO₂N(R^T)₂or-NR^TSO₂R^T(ii) a Wherein

Each R^TIndependently is hydrogen or unsubstituted C_1-6An aliphatic group; or

Any two R on the same substituent or different substituents^TThe groups together with the atoms to which each group is attached optionally form a 3-8 membered saturated or partially unsaturated monocyclic, or 5-6 membered monocyclic aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfurA seed; wherein said monocyclic ring is optionally substituted with 1-3 independent substituents selected from the group consisting of: -R^R、-T-Ar¹Halogen, oxo, thio, -OR^R、-SR^R、-N(R^R)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R^R、-COR^R、-CON(R^R)₂、-OCOR^R、-NR^RCOR^R、-SO₂R^R、-SO₂N(R^R)₂or-NR^RSO₂R^R(ii) a Wherein

Each R^RIndependently is hydrogen or unsubstituted C_1-6An aliphatic group;

t is (CH)₂)_w；

w is 0 to 2;

Ar¹selected from a 3-8 membered saturated or partially unsaturated ring, a 5-6 membered aromatic ring, a 3-7 membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein

Ar¹Optionally substituted with 1-3 independent substituents: -R^WOxo, thio, -CO₂R^W、-OR^W、-N(R^W)₂、-SR^W、-NO₂Halogen, -CN, -C_1-4Haloalkyl, -C_1-4Haloalkoxy, -C (O) N (R)^W)₂、-NR^WC(O)R^W、-SO₂R^W、-SO₂N(R^W)₂、-NR^WSO₂R^W、-NR^WCON(R^W)₂、-NR^WCO₂R^W、-COR^W、-OCOR^W、-OCON(R^W)₂、-SOR^W、-NR^WSO₂N(R^W)₂、-COCOR^W、-COCH₂COR^W、-OP(O)(OR^W)₂、-P(O)(OR^W)₂、-PO(OR^W)(R^W)、-P(O)(R^W)₂or-OP (O) (R)^W)₂(ii) a Wherein

R^WIs hydrogen or unsubstituted C_1-6An aliphatic group;

R^Qselected from halogen, -R^S、-N(R^S)₂、-SR^S、-OR^S、C_3-10Alicyclic group, C_6-10Aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, oxo, thioxo, -C_1-4Haloalkoxy, -C_1-4Haloalkyl, -NO₂、-CN、-CF₃、-OCF₃、-CO₂R^S、-COR^S、-OC(O)R^Sor-NR^SC(O)R^S(ii) a Wherein

R^SIs hydrogen or unsubstituted C_1-6An aliphatic group; or

Any two R on the same substituent or different substituents^QOr two R^SA group, or R^QGroup and R^SAny combination of groups, together with one or more atoms to which each group is attached, optionally form a 3-8 membered saturated or partially unsaturated monocyclic, or 5-6 membered monocyclic aromatic ring; each ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein any of said monocyclic rings is optionally substituted with 1-3 independent substituents selected from the group consisting of: r⁰Halogen, oxo, thio, -OR⁰、-SR⁰、-N(R⁰)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R⁰、-COR⁰、-CON(R⁰)₂、-OCOR⁰、-NR⁰COR⁰、-SO₂R⁰、-SO₂N(R⁰)₂or-NR⁰SO₂R⁰(ii) a Wherein

R⁰Is hydrogen or unsubstituted C_1-6An aliphatic group;

r' is independently selected from hydrogen or C_1-8Aliphatic radical, C_6-10Aryl, heteroaryl ring having 5-10 ring atoms, or heterocyclic ring having 3-10 ring atoms, or wherein R and R 'together with the atom or atoms to which they are attached, or 2R' together with the atoms to which they are attached, form a 5-8 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein said C_1-8Aliphatic radical, C_6-10The aryl, heteroaryl ring or heterocycle is optionally substituted with 1-3 independent substituents selected from the group consisting of: r^IHalogen, oxo, thio, -OR^I、-SR^I、-N(R^I)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R^I、-COR^I、-CONHR^I、-OCOR^I、-NR^ICOR^I、-SO₂R^I、-SO₂N(R^I)₂or-NR^ISO₂R^I(ii) a Wherein

R^IIs hydrogen or unsubstituted C_1-6An aliphatic group; but instead of the other end of the tube

With the proviso that the following compounds are excluded:

3- (4-chloro-3-methyl-isoxazol-5-ylaminosulfonyl) -thiophene-2-carboxylic acid (3-methanesulfonylamino-2, 4, 6-trimethyl-phenyl) -amide [ and the trifluoroacetate salt of 1 ];

2.2-methyl-pyridine-3, 5-dicarboxylic acid 5- [ (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -amide ]3- { [4- (pyridin-2-ylmethoxy) -phenyl ] -amide };

3.2-methyl-pyridine-3, 5-dicarboxylic acid 5- [ (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -amide ]3- { [4- (pyridin-4-ylmethoxy) -phenyl ] -amide };

1- (4-chloro-phenyl) -5-hydroxy-1H-pyrazole-4-carboxylic acid (3-methanesulfonyl-phenyl) -amide;

5-acetyl-1- (4-chloro-phenyl) -1H-pyrazole-4-carboxylic acid (3-methanesulfonyl-phenyl) -amide;

1- (4-chlorophenyl) -N- (3- (methylsulfonyl) phenyl) -5-vinyl-1H-pyrazole-4-carboxamide;

1- (4-chloro-phenyl) -5-cyano-1H-pyrazole-4-carboxylic acid (3-methanesulfonyl-phenyl) -amide;

1- (4-chloro-phenyl) -5-methyl-1H-pyrazole-3-carboxylic acid (3-methanesulfonyl-phenyl) -amide;

1-cyclohexyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-methanesulfonyl-phenyl) -amide;

1-p-tolyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-methanesulfonyl-phenyl) -amide;

1-m-tolyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-methanesulfonyl-phenyl) -amide;

1- (3-chloro-phenyl) -5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-methanesulfonyl-phenyl) -amide;

1- (1-benzyl-piperidin-4-yl) -5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (3-methanesulfonyl-phenyl) -amide;

5-chloro-1H-indole-2-carboxylic acid {3- [ (3-bromo-thiophene-2-carbonyl) -amino ] -5-ethanesulfonyl-2-hydroxy-phenyl } -amide;

15.5-chloro-1H-indole-2-carboxylic acid {3- [ (3-chloro-4-methanesulfonyl-thiophene-2-carbonyl) -amino ] -5-ethanesulfonyl-2-hydroxy-phenyl } -amide;

16.5-chloro-1H-indole-2-carboxylic acid { 5-ethanesulfonyl-2-hydroxy-3- [ (4-methyl- [1, 2, 3] thiadiazole-5-carbonyl) -amino ] -phenyl } -amide;

2- (4-fluoro-benzylamino) -N- (3-methanesulfonylamino-5-trifluoromethyl-phenyl) -nicotinamide;

n- (3-methanesulfonylamino-5-trifluoromethyl-phenyl) -2- [ (2-methylamino-pyrimidin-4-ylmethyl) -amino ] -nicotinamide;

n- (3-methanesulfonylamino-5-trifluoromethyl-phenyl) -2- [ (pyridin-4-ylmethyl) -amino ] -nicotinamide;

20.5-chloro-pyridine-2-carboxylic acid { 5-methanesulfonylamino-2- [4- (2-oxo-piperidin-1-yl) -phenylcarbamoyl ] -phenyl } -amide;

3- (4-chloro-3-methyl-isoxazol-5-ylaminosulfonyl) -thiophene-2-carboxylic acid (3-methanesulfonylamino-2, 4, 6-trimethyl-phenyl) -amide;

5-thiazolecarboxamide, N- [ 2-chloro-5- (methylsulfonyl) phenyl ] -2- [ (4-chlorophenoxy) methyl ] -4-methyl-;

3-pyridinecarboxamide, N- [3- (methylsulfonyl) phenyl ] -6- (2, 2, 2-trifluoroethoxy) -;

2H-1, 2, 3-triazole-4-carboxamide, 5-methyl-N- [3- (methylsulfonyl) phenyl ] -2-phenyl-;

2-thiophenecarboxamide, 5-methyl-N- [3- (methylsulfonyl) phenyl ] -;

3-furancarboxamide, 2, 4, 5-trimethyl-N- [3- (methylsulfonyl) phenyl ] -;

27.1H-pyrrole-3-carboxylic acid, 2, 4-dimethyl-5- [ [ [3- (methylsulfonyl) phenyl ] amino ] carbonyl ] -, methyl ester;

2-thiophenecarboxamide, 4, 5-dibromo-N- [5- (ethanesulfonyl) -2-hydroxyphenyl ] -;

29.3, 5-pyridinedicarboxamide, N5- [5- (1, 1-dimethylethyl) -2-methoxy-3- [ (methylsulfonyl) amino ] phenyl ] -2-methyl-N3- [4- (2-pyridylmethoxy) phenyl ] -;

3, 5-pyridinedicarboxamide, N5- [5- (1, 1-dimethylethyl) -2-methoxy-3- [ (methylsulfonyl) amino ] phenyl ] -2-methyl-N3- [4- (4-pyridylmethoxy) phenyl ] -;

2-pyridinecarboxamide, N- [3- (2-amino-5, 6-dihydro-4-methyl-4H-1, 3-thiazin-4-yl) -5- (methylsulfonyl) phenyl ] -5- (trifluoromethyl) -;

2-pyridinecarboxamide, N- [3- (2-amino-5, 6-dihydro-4-methyl-4H-1, 3-thiazin-4-yl) -5- (methylsulfonyl) phenyl ] -5-chloro-;

2-pyridinecarboxamide, N- [3- (2-amino-5, 6-dihydro-4-methyl-4H-1, 3-thiazin-4-yl) -5- (methylsulfonyl) phenyl ] -5-fluoro-;

34.5-thiazolecarboxamide, 4-methyl-N- [3- (methylsulfonyl) phenyl ] -2-phenyl-;

35.1H-pyrrole-3-carboxylic acid, 2-ethyl-4-methyl-5- [ [ [3- (methylsulfonyl) phenyl ] amino ] carbonyl ] -, methyl ester;

2-thiophenecarboxamide, N- [3- (methylsulfonyl) phenyl ] -3-phenyl-;

3-pyridinecarboxamide, 5-bromo-N- [3- (methylsulfonyl) phenyl ];

4-thiazolecarboxamide, N- [5- (ethylsulfonyl) -2-hydroxyphenyl ] -2- [ (4-methylphenoxy) methyl ] -;

2-furancarboxamide, N- [3- (methylsulfonyl) phenyl ] -5- (phenoxymethyl) -;

1H-pyrrole-3-carboxamide, 1-cyclopropyl-N- [3- [ [ (4-fluorophenyl) sulfonyl ] amino ] -4-methoxyphenyl ] -2, 5-dimethyl-;

3-furancarboxamide, 2, 5-dimethyl-N- [3- (methylsulfonyl) phenyl ] -;

4-pyridinecarboxamide, N- [3- (methylsulfonyl) phenyl ] -;

3.3-pyridazinecarboxamide, N- [3- [ [ (4-fluorophenyl) sulfonyl ] amino ] -4-methoxyphenyl ] -1, 4, 5, 6-tetrahydro-1-methyl-6-oxo-;

3-pyridazinecarboxamide, N- [ 2-chloro-5- (methylsulfonyl) phenyl ] -1- (2-chlorophenyl) -1, 4-dihydro-6-methyl-4-oxo-;

45.1H-imidazole-5-carboxamide, N- [ 2-chloro-5- (methylsulfonyl) phenyl ] -2- (methylthio) -1-phenyl-;

3-thiophenecarboxamide, 2, 5-dichloro-N- [ 2-chloro-5- (methylsulfonyl) phenyl ] -;

4-isoxazolecarboxamide, N- [ 2-chloro-5- (methylsulfonyl) phenyl ] -3-ethyl-5-methyl-;

48.1H-imidazole-5-carboxamide, N- [ 2-chloro-5- (methylsulfonyl) phenyl ] -1- (4-fluorophenyl) -2- (methylthio) -;

2-furancarboxamide, 5- (4-acetylphenyl) -N- [ 2-chloro-5- (methylsulfonyl) phenyl ] -;

50.2-pyridinecarboxamide, 3, 4, 5-trichloro-N- [ 2-chloro-5- (methylsulfonyl) phenyl ] -;

51.3-pyridinecarboxamide, 2-methyl-N- [3- (methylsulfonyl) phenyl ] -6-phenyl-;

3-furancarboxamide, N- [5- (ethanesulfonyl) -2-hydroxyphenyl ] -;

2H-1, 2, 3-triazole-4-carboxamide, N- [ 2-chloro-5- (methylsulfonyl) phenyl ] -5-methyl-2-phenyl-;

54.2-Furancarboxamide, N- [3- [ (methylsulfonyl) amino ] phenyl ] -N- [1- (2-phenylethyl) -4-piperidinyl ] -, ethanedioic acid salt (1: 1);

2-furancarboxamide, N- [3- [ (methylsulfonyl) amino ] phenyl ] -N- [1- (2-phenylethyl) -4-piperidinyl ] -;

56.1H-pyrazole-5-carboxamide, 1- [3- [ [ [ (2S) -2-amino-1-oxopropyl ] amino ] methyl ] phenyl ] -N- [3- (methylsulfonyl) phenyl ] -3- (trifluoromethyl) -;

4-pyrimidinecarboxamide, 6- [ (2-methoxyethyl) methylamino ] -N- [3- (methylsulfonyl) phenyl ] -2- (4-morpholinyl) -;

58.2-furancarboxamide, N- [3- (methylsulfonyl) phenyl ] -;

59.1H-pyrrole-3-carboxamide, 2, 5-dimethyl-N- [3- [ (methylsulfonyl) amino ] phenyl ] -1- [2- (trifluoromethyl) phenyl ] -;

1.1H-pyrazole-3-carboxamide, N- [5- (ethanesulfonyl) -2-hydroxyphenyl ] -4-methoxy-1-phenyl-;

2-pyridinecarboxamide, N- [5- (ethanesulfonyl) -2-hydroxyphenyl ] -;

62.3-pyridinecarboxamide, 5-bromo-N- [5- (ethylsulfonyl) -2-hydroxyphenyl ] -;

63.1H-pyrazole-4-carboxamide, N- [3- (methylsulfonyl) phenyl ] -1- (phenylmethyl) -3- (2-thienyl) -;

64.1H-pyrazole-4-carboxamide, 5-chloro-N- [ 2-chloro-5- (methylsulfonyl) phenyl ] -3-methyl-1- [ (4-methylphenyl) methyl ] -;

65.2-thiophenecarboxamide, N- [ 2-chloro-5- (methylsulfonyl) phenyl ] -5- (4-fluorophenyl) -;

4-oxazole carboxamide, N- [ 2-chloro-5- (methylsulfonyl) phenyl ] -5-methyl-2-phenyl-;

67. pyrazinecarboxamide, N- [ 2-chloro-5- (methylsulfonyl) phenyl ] -5-methyl-;

68.4-Thiazolecarboxamide, N- [3- [ (methylsulfonyl) amino ] phenyl ] -2- [ [3- (4-morpholinyl) propyl ] (2-thienylcarbonyl) amino ] -;

69.1H-imidazole-5-carboxamide, N- [ 2-chloro-5- (methylsulfonyl) phenyl ] -1- (4-fluorophenyl) -;

4-carboxamide, N- [ 2-chloro-5- (methylsulfonyl) phenyl ] -2- (2, 4-dimethylphenyl) -5-methyl-;

2H-1, 2, 3-triazole-4-carboxamide, N- [ 2-chloro-5- (methylsulfonyl) phenyl ] -2-phenyl-;

72.3-isoxazolecarboxamide, N- [ 2-chloro-5- (methylsulfonyl) phenyl ] -5-methyl-;

73.4-isoxazolecarboxamide, N- [ 2-chloro-5- (methylsulfonyl) phenyl ] -5-methyl-3-phenyl-;

74.3-pyridazinecarboxamide, N- [ 2-chloro-5- (methylsulfonyl) phenyl ] -1, 4, 5, 6-tetrahydro-6-oxo-1-phenyl-;

75.4-isoxazolecarboxamide, N- [ 2-chloro-5- (methylsulfonyl) phenyl ] -3, 5-dimethyl-;

2-furancarboxamide, N- [2- [1- (1-methylethyl) -1H-pyrazol-4-yl ] -5- (methylsulfonyl) phenyl ] -;

77.1H-1, 2, 4-triazole-3-carboxamide, N- [ 2-chloro-5- (methylsulfonyl) phenyl ] -1, 5-diphenyl-;

1H-pyrrole-2-carboxamide, N- [ 2-chloro-5- (methylsulfonyl) phenyl ] -1-methyl-;

3-pyridinecarboxamide, N- [3, 5-bis (methylsulfonyl) phenyl ] -6- (3, 3-dimethyl-1-butanoyl) -;

80.3-pyridinecarboxamide, 6- (3, 3-dimethyl-1-butanoyl) -N- [3- (methylsulfonyl) phenyl ] -;

3-pyridinecarboxamide, N- [ 2-chloro-5- (methylsulfonyl) phenyl ] -2- (phenylthio) -;

82.3-furancarboxamide, N- [ 2-chloro-5- (methylsulfonyl) phenyl ] -2, 5-dimethyl-;

83.4-pyridinecarboxamide, N- [5- (ethylsulfonyl) -2-hydroxyphenyl ] -;

2-furancarboxamide, N- [ 2-chloro-5- (methylsulfonyl) phenyl ] -;

2-thiophenecarboxamide, N- [ 2-chloro-5- (methylsulfonyl) phenyl ] -;

86.1H-pyrazole-4-carboxamide, 5-acetyl-1- (4-chlorophenyl) -N- [3- (methylsulfonyl) phenyl ] -;

87.1H-pyrazole-4-carboxamide, 1- (4-chlorophenyl) -5-vinyl-N- [3- (methylsulfonyl) phenyl ] -;

88.1H-pyrazole-4-carboxamide, 1- (4-chlorophenyl) -5-cyano-N- [3- (methylsulfonyl) phenyl ] -;

89.1H-pyrazole-4-carboxamide, 1- (4-chlorophenyl) -5-hydroxy-N- [3- (methylsulfonyl) phenyl ] -;

1.1H-pyrazole-3-carboxamide, 1- (4-chlorophenyl) -5-methyl-N- [3- (methylsulfonyl) phenyl ] -;

1H-pyrazole-4-carboxamide, N- [3- (methylsulfonyl) phenyl ] -1- [1- (phenylmethyl) -4-piperidinyl ] -5- (trifluoromethyl) -;

92.1H-pyrazole-4-carboxamide, 1-cyclohexyl-N- [3- (methylsulfonyl) phenyl ] -5- (trifluoromethyl) -;

1H-pyrazole-4-carboxamide, 1- (4-methylphenyl) -N- [3- (methylsulfonyl) phenyl ] -5- (trifluoromethyl) -;

1H-pyrazole-4-carboxamide, 1- (3-methylphenyl) -N- [3- (methylsulfonyl) phenyl ] -5- (trifluoromethyl) -;

95.1H-pyrazole-4-carboxamide, 1- (3-chlorophenyl) -N- [3- (methylsulfonyl) phenyl ] -5- (trifluoromethyl) -;

96.1H-indole-2-carboxamide, N- [3- [ [ (3-bromo-2-thienyl) carbonyl ] amino ] -5- (ethanesulfonyl) -2-hydroxyphenyl ] -5-chloro-;

97.1H-indole-2-carboxamide, 5-chloro-N- [3- [ [ [ 3-chloro-4- (propylsulfonyl) -2-thienyl ] carbonyl ] amino ] -5- (ethanesulfonyl) -2-hydroxyphenyl ] -;

98.1H-indole-2-carboxamide, 5-chloro-N- [3- [ [ [ 3-chloro-4- (methylsulfonyl) -2-thienyl ] carbonyl ] amino ] -5- (ethylsulfonyl) -2-hydroxyphenyl ] -;

99.1H-indole-2-carboxamide, 5-chloro-N- [5- (ethanesulfonyl) -2-hydroxy-3- [ [ (4-methyl-1, 2, 3-thiadiazol-5-yl) carbonyl ] amino ] phenyl ] -;

3-pyridinecarboxamide, N- [3- [ (methylsulfonyl) amino ] phenyl ] -2- [ (4-pyridylmethyl) thio ] -;

101.2-thiophenecarboxamide, 5- (2-benzothiazolyl) -N- [ 2-chloro-5- (methylsulfonyl) phenyl ] -;

3-furancarboxamide, N- [4- [2- [ (1-methylethyl) amino ] ethoxy ] -3- [ (methylsulfonyl) amino ] phenyl ] -;

103.2-thiophenecarboxamide, N- [3- (methylsulfonyl) phenyl ] -;

104.3-thiophenecarboxamide, N- [ 4-methyl-3- [ (methylsulfonyl) amino ] phenyl ] -;

105.4-isoxazolecarboxamide, 5-methyl-N- [ 4-methyl-3- [ (methylsulfonyl) amino ] phenyl ] -3-phenyl-;

106.1, 2, 3-thiadiazole-5-carboxamide, 4-methyl-N- [ 4-methyl-3- [ (methylsulfonyl) amino ] phenyl ] -;

4-isoxazolecarboxamide, 3, 5-dimethyl-N- [ 4-methyl-3- [ (methylsulfonyl) amino ] phenyl ];

108. pyrazinecarboxylic acid, 3- [ [ [5- (ethanesulfonyl) -2-hydroxyphenyl ] amino ] carbonyl ] -;

109.1H-pyrazole-5-carboxamide, 3- (1, 1-dimethylethyl) -1-ethyl-N- [3- (methylsulfonyl) phenyl ] -;

2-furancarboxamide, N- [3- [ methyl (methylsulfonyl) amino ] phenyl ] -;

3.3-pyridinecarboxamide, N- [3- [ (methylsulfonyl) amino ] -5- (trifluoromethyl) phenyl ] -2- [ (4-pyridylmethyl) amino ] -;

112.3-pyridinecarboxamide, 2- [ [ [2- (methylamino) -4-pyridinyl ] methyl ] amino ] -N- [3- [ (methylsulfonyl) amino ] -5- (trifluoromethyl) phenyl ] -;

113.3-pyridinecarboxamide, 2- [ [ [2- (methylamino) -4-pyrimidinyl ] methyl ] amino ] -N- [3- [ (methylsulfonyl) amino ] -5- (trifluoromethyl) phenyl ] -;

114.3-pyridinecarboxamide, 2- [ [ (2-methoxy-4-pyridinyl) methyl ] amino ] -N- [3- [ (methylsulfonyl) amino ] -5- (trifluoromethyl) phenyl ];

115.3-pyridinecarboxamide, 2- (1H-indazol-6-ylamino) -N- [3- [ (methylsulfonyl) amino ] -5- (trifluoromethyl) phenyl ] -;

116.2-thiophenecarboxamide, N- [ 4-methyl-3- [ (methylsulfonyl) amino ] phenyl ] -;

117.3-pyridinecarboxamide, 2- [ [ (4-fluorophenyl) methyl ] amino ] -N- [3- [ (methylsulfonyl) amino ] -5- (trifluoromethyl) phenyl ] -;

118.1H-pyrazole-5-carboxamide, N- [3- (methylsulfonyl) phenyl ] -1-phenyl-;

119.1H-pyrazole-4-carboxamide, 1- (4-chlorophenyl) -N- [3- [ (methylsulfonyl) amino ] phenyl ] -5- (trifluoromethyl) -;

120.1H-pyrazole-4-carboxamide, 1- (4-chlorophenyl) -N- [3- [ (2-hydroxyethyl) sulfonyl ] phenyl ] -5- (trifluoromethyl) -;

1H-pyrazole-4-carboxamide, 1- (3, 4-difluorophenyl) -N- [3- (methylsulfonyl) phenyl ] -5- (trifluoromethyl) -;

122.1H-pyrazole-4-carboxamide, 1- (3-fluorophenyl) -N- [3- (methylsulfonyl) phenyl ] -5- (trifluoromethyl) -;

123.1H-pyrazole-4-carboxamide, N- [3- (methylsulfonyl) phenyl ] -1- [4- (trifluoromethoxy) phenyl ] -5- (trifluoromethyl);

124.1H-pyrazole-4-carboxamide, N- [3- (methylsulfonyl) phenyl ] -1- (2-pyrimidinyl) -5- (trifluoromethyl) -;

125.1H-pyrazole-4-carboxamide, 1- (4-chlorophenyl) -N- [3- (methylsulfonyl) phenyl ] -N-2-propenyl-5- (trifluoromethyl) -;

126.1H-pyrazole-4-carboxamide, 1- (4-chlorophenyl) -N- (cyanomethyl) -N- [3- (methylsulfonyl) phenyl ] -5- (trifluoromethyl) -;

127. glycine, N- [ [1- (4-chlorophenyl) -5- (trifluoromethyl) -1H-pyrazol-4-yl ] carbonyl ] -N- [3- (methylsulfonyl) phenyl ] -, ethyl ester;

128.1H-pyrazole-4-carboxamide, 1- (4-chlorophenyl) -N-ethyl-N- [3- (methylsulfonyl) phenyl ] -5- (trifluoromethyl) -;

129.1H-pyrazole-4-carboxamide, 1- (1, 6-dihydro-6-oxo-3-pyridazinyl) -N- [3- (methylsulfonyl) phenyl ] -5- (trifluoromethyl) -;

1.1H-pyrazole-4-carboxamide, 1- (6-chloro-2-pyridyl) -N- [3- (methylsulfonyl) phenyl ] -5- (trifluoromethyl) -;

131.1H-pyrazole-4-carboxamide, N- [3- (methylsulfonyl) phenyl ] -5- (trifluoromethyl) -1- [5- (trifluoromethyl) -2-pyridyl ] -;

132.1H-pyrazole-4-carboxamide, N- [3- (methylsulfonyl) phenyl ] -1- (2-pyridyl) -5- (trifluoromethyl) -;

1H-pyrazole-4-carboxamide, 1- (4-chlorophenyl) -N- [ 2-fluoro-5- (methylsulfonyl) phenyl ] -N-methyl-5- (trifluoromethyl) -;

134.1H-pyrazole-4-carboxamide, 1- (4-chlorophenyl) -N- [5- (ethanesulfonyl) -2-methoxyphenyl ] -N-methyl-5- (trifluoromethyl) -;

1.1H-pyrazole-4-carboxamide, 1- (4-fluorophenyl) -5-methyl-N- [3- (methylsulfonyl) phenyl ] -;

1H-pyrazole-4-carboxamide, 1- (4-methoxyphenyl) -5-methyl-N- [3- (methylsulfonyl) phenyl ] -;

1H-pyrazole-4-carboxamide, 5-methyl-N- [3- (methylsulfonyl) phenyl ] -1-phenyl-;

138.1H-pyrazole-4-carboxamide, 1- (4-methoxyphenyl) -N- [3- (methylsulfonyl) phenyl ] -;

139.1H-pyrazole-4-carboxamide, 1- (4-fluorophenyl) -N- [3- (methylsulfonyl) phenyl ] -;

140.1H-pyrazole-4-carboxamide, 1- (4-bromophenyl) -N- [3- (methylsulfonyl) phenyl ] -;

141.1H-pyrazole-4-carboxamide, 1- (3, 4-dichlorophenyl) -N- [3- (methylsulfonyl) phenyl ] -;

142.1H-pyrazole-4-carboxamide, 1- (2-chlorophenyl) -N- [3- (methylsulfonyl) phenyl ] -;

143.1H-pyrazole-4-carboxamide, 1- (4-methylphenyl) -N- [3- (methylsulfonyl) phenyl ] -;

144.1H-pyrazole-4-carboxamide, N- [3- (methylsulfonyl) phenyl ] -1- (phenylmethyl);

145.1H-pyrazole-4-carboxamide, 1- (4-chlorophenyl) -N- [3- (methylsulfonyl) phenyl ] -;

146.1H-pyrazole-4-carboxamide, 1- (3-chlorophenyl) -N- [3- (methylsulfonyl) phenyl ] -;

147.1H-pyrazole-4-carboxamide, 1- [4- [ (aminoiminomethyl) amino ] phenyl ] -N- [3- (methylsulfonyl) phenyl ] -5- (trifluoromethyl) -;

148.1H-pyrazole-4-carboxamide, 1- (4-aminophenyl) -N- [3- (methylsulfonyl) phenyl ] -5- (trifluoromethyl) -;

149.1H-pyrazole-4-carboxamide, N- [3- (methylsulfonyl) phenyl ] -1- (4-nitrophenyl) -5- (trifluoromethyl) -;

150.1H-pyrazole-4-carboxamide, 1- (4-chlorophenyl) -N- [ 2-fluoro-5- (methylsulfonyl) phenyl ] -5- (trifluoromethyl) -;

151.1H-pyrazole-4-carboxamide, 1- (4-chlorophenyl) -N- [3- (methylsulfonyl) phenyl ] -5-propyl-

152.1H-pyrazole-4-carboxamide, 5-chloro-1-methyl-N- [3- (methylsulfonyl) phenyl ] -;

153.1H-pyrazole-4-carboxamide, 1- (4-chlorophenyl) -N- [5- (ethanesulfonyl) -2-methoxyphenyl ] -5- (trifluoromethyl) -;

154.1H-pyrazole-4-carboxamide, 1- (4-chlorophenyl) -N-methyl-N- [3- (methylsulfonyl) phenyl ] -5- (trifluoromethyl) -;

155.1H-pyrazole-4-carboxamide, 1- (4-fluorophenyl) -N- [3- (methylsulfonyl) phenyl ] -5- (trifluoromethyl) -;

156.1H-pyrazole-4-carboxamide, N- [3- (methylsulfonyl) phenyl ] -1-phenyl-5- (trifluoromethyl) -;

157.1H-pyrazole-4-carboxamide, N- [3- (methylsulfonyl) phenyl ] -1-phenyl-5-propyl-;

158.1H-pyrazole-4-carboxamide, 1- (4-chlorophenyl) -N- [3- (methylsulfonyl) phenyl ] -5- (trifluoromethyl) -;

159.2-pyridinecarboxamide, 5-chloro-N- [5- [ (methylsulfonyl) amino ] -2- [ [ [4- (2-oxo-1-piperidinyl) phenyl ] amino ] carbonyl ] phenyl ] -;

160.1H-pyrazole-4-carboxamide, 1-methyl-N- [3- (methylsulfonyl) phenyl ] -3- [3- (trifluoromethyl) phenoxy ] -;

161.2-thiophenecarboxamide, N- [5- (ethylsulfonyl) -2-hydroxyphenyl ] -;

2-thiophenecarboxamide, 3- [ [ (3, 4-dimethyl-5-isoxazolyl) amino ] sulfonyl ] -N- [2, 4, 6-trimethyl-3- [ (methylsulfonyl) amino ] phenyl ] -;

2-thiophenecarboxamide, 3- (4-chloro-3-methyl-5-isoxazolyl) -N- [2, 4, 6-trimethyl-3- [ (methylsulfonyl) amino ] phenyl ] -;

164.2-thiophenecarboxamide, N- [2- (4-methyl-1-piperazinyl) -5- (methylsulfonyl) phenyl ] -;

165.1H-pyrazole-5-carboxamide, N- [ 3-fluoro-2- (methylsulfonyl) [1, 1' -biphenyl ] -4-yl ] -1- [3- (3-pyridyl) phenyl ] -3- (trifluoromethyl) -;

166.2-thiophenecarboxamide, 3- [ [ (4, 5-dimethyl-3-isoxazolyl) amino ] sulfonyl ] -N- [2, 4, 6-trimethyl-3- [ (methylsulfonyl) amino ] phenyl ] -;

167.2-thiophenecarboxamide, 3- [ [ (4, 5-dimethyl-3-isoxazolyl) amino ] sulfonyl ] -N- [2, 4, 6-trimethyl-3- (methylsulfonyl) phenyl;

2-thiophenecarboxamide, 3- [ [ (3, 4-dimethyl-5-isoxazolyl) amino ] sulfonyl ] -N- [2, 4, 6-trimethyl-3- (methylsulfonyl) phenyl ] -;

169.2-thiophenecarboxamide, 3- [ [ (3-methoxypyrazinyl) amino ] sulfonyl ] -N- [2, 4, 6-trimethyl-3- [ (methylsulfonyl) amino ] phenyl ] -, monosodium salt;

170.2-thiophenecarboxamide, 3- [ (2, 1, 3-benzothiadiazol-5-ylamino) sulfonyl ] -N- [2, 4, 6-trimethyl-3- [ (methylsulfonyl) amino ] phenyl ] -, monosodium salt;

171.2-thiophenecarboxamide, 3- [ [ (4, 5-dimethyl-3-isoxazolyl) amino ] sulfonyl ] -N- [2, 4, 6-trimethyl-3- [ (methylsulfonyl) amino ] phenyl ] -, monosodium salt;

172.2-thiophenecarboxamide, 3- [ [ (4-chloro-3-methyl-5-isoxazolyl) amino ] sulfonyl ] -N- [2, 4, 6-trimethyl-3- [ (methylsulfonyl) amino ] phenyl ] -, monosodium salt;

173.2-thiophenecarboxamide, 3- [ [ (4, 5-dimethyl-3-isoxazolyl) amino ] sulfonyl ] -N- [2, 4, 6-trimethyl-3- (methylsulfonyl) phenyl ] -, monosodium salt;

174.2-thiophenecarboxamide, 3- [ [ (3, 4-dimethyl-5-isoxazolyl) amino ] sulfonyl ] -N- [2, 4, 6-trimethyl-3- (methylsulfonyl) phenyl ] -, monosodium salt;

2-thiophenecarboxamide, 3- [ [ (4-chloro-3-methyl-5-isoxazolyl) amino ] sulfonyl ] -N- [2, 4, 6-trimethyl-3- (methylsulfonyl) phenyl ] -, monosodium salt;

176.2-thiophenecarboxamide, N- [5- [ (1-ethylpropyl) sulfonyl ] -2-methoxyphenyl ] -;

177.2-furancarboxamide, N- [5- [ (1-ethylpropyl) sulfonyl ] -2-methoxyphenyl ] -;

178.4-isoxazolecarboxamide, 3- (2, 6-dichlorophenyl) -N- [5- [ (1-ethylpropyl) sulfonyl ] -2-methoxyphenyl ] -5-methyl-;

179.4-isoxazolecarboxamide, 3- (2-chlorophenyl) -N- [5- [ (1-ethylpropyl) sulfonyl ] -2-methoxyphenyl ] -5-methyl-;

180.3-pyridinecarboxamide, N- [ 2-chloro-5- (methylsulfonyl) phenyl ] -;

181.2, 3-pyridinedicarboxamide, 6-methyl-N3- [ 2-methyl-3- (methylsulfonyl) phenyl ] -N2-propyl-;

2-furancarboxamide, N- [5- (ethylsulfonyl) -2-hydroxyphenyl ] -5- [ (5, 6, 7, 8-tetrahydro-3, 5, 5,8, 8-pentamethyl-2-naphthyl) methyl ] -;

183.3-furancarboxamide, N- [4- [2- [ (1-methylethyl) amino ] ethoxy ] -3- [ (methylsulfonyl) amino ] phenyl ] -, monohydrochloride;

184.2-thiophenecarboxamide, 3- [ [ (3-methoxy-2-pyrazinyl) amino ] sulfonyl ] -N- [2, 4, 6-trimethyl-3- [ (methylsulfonyl) amino ] phenyl ] -;

185.2-thiophenecarboxamide, 3- [ (2, 1, 3-benzothiadiazol-5-ylamino) sulfonyl ] -N- [2, 4, 6-trimethyl-3- [ (methylsulfonyl) amino ] phenyl ] -;

186.2-thiophenecarboxamide, 3- [ [ (3, 4-dimethyl-5-isoxazolyl) amino ] sulfonyl ] -N- [2, 4, 6-trimethyl-3- [ (methylsulfonyl) amino ] phenyl ] -, monosodium salt;

2-thiophenecarboxamide, 3- [ [ (4-chloro-5-methyl-3-isoxazolyl) amino ] sulfonyl ] -N- [2, 4, 6-trimethyl-3- [ (methylsulfonyl) amino ] phenyl ] -;

188.2-thiophenecarboxamide, 3- [ [ (4-chloro-3-methyl-5-isoxazolyl) amino ] sulfonyl ] -N- [2, 4, 6-trimethyl-3- [ (methylsulfonyl) amino ] phenyl ] -;

189.2-thiophenecarboxamide, 3- [ [ (4-chloro-3-methyl-5-isoxazolyl) amino ] sulfonyl ] -N- [2, 4, 6-trimethyl-3- (methylsulfonyl) phenyl ] -;

190.1H-pyrazole-3-carboxamide, N- [3- [ (butylsulfonyl) amino ] phenyl ] -4- [ (3-ethyl-4, 5-dimethyl-2 (3H) -oxazolylidene) ethylidene ] -4, 5-dihydro-5-oxo-1- (tetrahydro-1, 1-dioxo-3-thienyl) -;

191.1H-pyrazole-5-carboxamide, 1-methyl-N- [3- (methylsulfonyl) phenyl ] -3- (trifluoromethyl) -;

192.1H-pyrazole-4-carboxylic acid, 3- (4-chlorophenyl) -4, 5-dihydro-4-methyl-1- [ [ [3- (methylsulfonyl) phenyl ] amino ] carbonyl ] -, methyl ester;

193.1H-tetrazole-5-carboxamide, N- [ 3-acetyl-2-hydroxy-5- (methylsulfonyl) phenyl ] -1- [ (4-methoxyphenyl) methyl ] -; and

194.1H-tetrazole-5-carboxamide, N- [ 3-acetyl-2-hydroxy-5- (methylsulfonyl) phenyl ] -.

In another embodiment, the invention provides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

ring B is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein ring B is optionally substituted with up to x R³Substitution;

X¹、X²、X³and X⁴Each independently is nitrogen or C-R⁴Provided that X is¹、X²、X³And X⁴Is not nitrogen at the same time;

R^Aselected from SO₂N(R²)₂、SO₂R¹、NR²SO₂R¹；

R¹Is C_1-6Aliphatic radical in which up to 2 atoms other than the atom bound to the nitrogen or oxygen atom are optionally O, S, NR^NOr C (O) instead;

each R²Independently hydrogen, or C_1-6Aliphatic radical in which up to 2 carbon atoms, other than the atom bound to the nitrogen atom, are optionally O, S, NR^NOr C (O) instead;

x is 0 to 4;

R^Neach independently selected from hydrogen or C_1-6An aliphatic group optionally substituted with 1-3 independent substituents selected from the group consisting of: -R^JOxo, thio, -CO₂R^J、-OR^J、-N(R^J)₂、-SR^J、-NO₂Halogen, -CN, -C_1-4Haloalkyl, -C_1-4Haloalkoxy, -C (O) N (R)^J)₂、-NR^JC(O)R^J、-SO₂R^J、-SO₂N(R^J)₂、-NR^JSO₂R^J、-NR^JCON(R^J)₂、-NR^JCO₂R^J、-COR^J、-OCOR^J、-OCON(R^J)₂、-SOR^J、-NR^JSO₂N(R^J)₂、-COCOR^J、-COCH₂COR^J、-OP(O)(OR^J)₂、-P(O)(OR^J)₂、-PO(OR^J)(R^J)、-P(O)(R^J)₂or-OP (O) (R)^J)₂(ii) a Wherein

R^JIs hydrogen or unsubstituted C_1-6An aliphatic group;

R³and R⁴Each independently is Q-R^X；

Q is a bond or C_1-6An aliphatic chain in which up to 3 methylene units of Q are optionally and independently replaced by: -NH-, -NR-, -O-, -S-, -CO-, -C₂-、-OC(O)-、-C(O)CO-、-C(O)-、-C(S)-、-C(O)NH-、-C(O)NR-、-C(＝N-CN)-、-NHCO-、-NRCO-、-NHC(O)O-、-NRC(O)O-、-SO₂NH-、-SO₂NR-、-NHSO₂-、-NRSO₂-、-NHC(O)NH-、-NRC(O)NH-、-NHC(O)NR-、-NRC(O)NR、-OC(O)NH-、-OC(O)NR-、-NHSO₂NH-、-NRSO₂NH-、-NHSO₂NR-、-NRSO₂NR-, -SO-or-SO₂-; wherein

Q is optionally substituted with 1-3 independent R^QAnd (3) substitution:

R^Xeach independently selected from-R', halogen, -NO₂、-CN、-OR′、-SR′、-N(R′)₂、-NR′C(O)R′、-NR′C(O)N(R′)₂、-NR′CO₂R′、-C(O)R′、-CO₂R′、-OC(O)R′、-C(O)N(R′)₂、-OC(O)N(R′)₂、-SOR′、-SO₂R′、-SO₂N(R′)₂、-NR′SO₂R′、-NR′SO₂N(R′)₂、-C(O)C(O)R′、-C(O)CH₂C(O)R′、-OP(O)(OR′)₂、-P(O)(OR′)₂、-PO(OR′)(R′)、-P(O)(R′)₂or-OP (O) (R')₂；

Each R is independently selected from hydrogen or C_1-6An aliphatic group optionally substituted with 1-3 independent substituents selected from the group consisting of: -R^T、-T-Ar¹Halogen, oxo, thio, -OR^T、-SR^T、-N(R^T)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R^T、-COR^T、-CON(R^T)₂、-OCOR^T、-NR^TCOR^T、-SO₂R^T、-SO₂N(R^T)₂or-NR^TSO₂R^T(ii) a Wherein

Each R^TIndependently is hydrogen or unsubstituted C_1-6An aliphatic group; or

Any two R on the same substituent or different substituents^TThe groups together with the atoms to which each group is attached optionally form a 3-8 membered saturated or partially unsaturated monocyclic, or 5-6 membered monocyclic aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein said monocyclic ring is optionally substituted with 1-3 independent substituents selected from the group consisting of: -R^R、-T-Ar¹Halogen, oxo, thio, -OR^R、-SR^R、-N(R^R)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R^R、-COR^R、-CON(R^R)₂、-OCOR^R、-NR^RCOR^R、-SO₂R^R、-SO₂N(R^R)₂or-NR^RSO₂R^R(ii) a Wherein

Each R^RIndependently is hydrogen or unsubstituted C_1-6An aliphatic group;

t is (CH)₂)_w；

w is 0 to 2;

Ar¹selected from a 3-8 membered saturated or partially unsaturated ring, a 5-6 membered aromatic ring, a 3-7 membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein

Ar¹Optionally substituted with 1-3 independent substituents: -R^WOxo, thio, -CO₂R^W、-OR^W、-N(R^W)₂、-SR^W、-NO₂Halogen, -CN, -C_1-4Haloalkyl, -C_1-4Haloalkoxy, -C (O) N (R)^W)₂、-NR^WC(O)R^W、-SO₂R^W、-SO₂N(R^W)₂、-NR^WSO₂R^W、-NR^WCON(R^W)₂、-NR^WCO₂R^W、-COR^W、-OCOR^W、-OCON(R^W)₂、-SOR^W、-NR^WSO₂N(R^W)₂、-COCOR^W、-COCH₂COR^W、-OP(O)(OR^W)₂、-P(O)(OR^W)₂、-PO(OR^W)(R^W)、-P(O)(R^W)₂or-OP (O) (R)^W)₂(ii) a Wherein

R^WIs hydrogen or unsubstituted C_1-6An aliphatic group;

R^Qselected from halogen, -R^S、-N(R^S)₂、-SR^S、-OR^S、C_3-10Alicyclic group, C_6-10Aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, oxo, thioxo, -C_1-4Haloalkoxy, -C_1-4Haloalkyl, -NO₂、-CN、-CF₃、-OCF₃、-CO₂R^S、-COR^S、-OC(O)R^Sor-NR^SC(O)R^S(ii) a Wherein

R^SIs hydrogen or unsubstituted C_1-6An aliphatic group; or

Any two R on the same substituent or different substituents^QOr two R^SA group, or R^QGroup and R^SAny combination of groups, together with one or more atoms to which each group is attached, optionally form a 3-8 membered saturated or partially unsaturated monocyclic, or 5-6 membered monocyclic aromatic ring; each ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein any of said monocyclic rings is optionally substituted with 1-3 independent substituents selected from the group consisting of: r⁰Halogen, oxo, thio, -OR⁰、-SR⁰、-N(R⁰)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R⁰、-COR⁰、-CON(R⁰)₂、-OCOR⁰、-NR⁰COR⁰、-SO₂R⁰、-SO₂N(R⁰)₂or-NR⁰SO₂R⁰(ii) a Wherein

R⁰Is hydrogen or unsubstituted C_1-6An aliphatic group;

r' is independently selected from hydrogen or C_1-8Aliphatic radical, C_6-10Aryl, heteroaromatic ring having 5 to 10 ring atoms, or having 3 to 10 ringsA heterocycle of atoms, or wherein R and R ', together with one or more atoms to which they are attached, or 2R' together with atoms to which they are attached, form a 5-8 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein said C_1-8Aliphatic radical, C_6-10The aryl, heteroaryl ring or heterocycle is optionally substituted with 1-3 independent substituents selected from the group consisting of: r^IHalogen, oxo, thio, -OR^I、-SR^I、-N(R^I)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R^I、-COR^I、-CONHR^I、-OCOR^I、-NR^ICOR^I、-SO₂R^I、-SO₂N(R^I)₂or-NR^ISO₂R^I(ii) a Wherein

R^IIs hydrogen or unsubstituted C_1-6An aliphatic group.

In another embodiment, the invention provides a compound of formula I':

or a pharmaceutically acceptable salt thereof, wherein:

ring B is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein ring B is optionally substituted with up to x R³Substitution;

X¹、X²、X³and X⁴Each independently is nitrogen or C-R⁴Provided that X is¹、X²、X³And X⁴Is not nitrogen at the same time;

R^Aselected from SO₂N(R²)₂Or NR²SO₂R¹；

R¹Is C_1-6Aliphatic radical in which up to 2 atoms other than the atom bound to the nitrogen or oxygen atom are optionally O, S, NR^NOr C (O) instead;

each R²Independently hydrogen, or C_1-6Aliphatic radical in which up to 2 carbon atoms, other than the atom bound to the nitrogen atom, are optionally O, S, NR^NOr C (O) instead;

x is 0 to 4;

R^Neach independently selected from hydrogen or C_1-6An aliphatic group optionally substituted with 1-3 independent substituents selected from the group consisting of: -R^JOxo, thio, -CO₂R^J、-OR^J、-N(R^J)₂、-SR^J、-NO₂Halogen, -CN, -C_1-4Haloalkyl, -C_1-4Haloalkoxy, -C (O) N (R)^J)₂、-NR^JC(O)R^J、-SO₂R^J、-SO₂N(R^J)₂、-NR^JSO₂R^J、-NR^JCON(R^J)₂、-NR^JCO₂R^J、-COR^J、-OCOR^J、-OCON(R^J)₂、-SOR^J、-NR^JSO₂N(R^J)₂、-COCOR^J、-COCH₂COR^J、-OP(O)(OR^J)₂、-P(O)(OR^J)₂、-PO(OR^J)(R^J)、-P(O)(R^J)₂or-OP (O) (R)^J)₂(ii) a Wherein

R^JIs hydrogen or unsubstituted C_1-6An aliphatic group;

R³and R⁴Each independently is Q-R^X；

Q is a bond or C_1-6An aliphatic chain in which up to 3 methylene units of Q are optionally and independently replaced by: -NH-, -NR-, -O-, -S-, -CO-, -C₂-、-OC(O)-、-C(O)CO-、-C(O)-、-C(S)-、-C(O)NH-、-C(O)NR-、-C(＝N-CN)-、-NHCO-、-NRCO-、-NHC(O)O-、-NRC(O)O-、-SO₂NH-、-SO₂NR-、-NHSO₂-、-NRSO₂-、-NHC(O)NH-、-NRC(O)NH-、-NHC(O)NR-、-NRC(O)NR、-OC(O)NH-、-OC(O)NR-、-NHSO₂NH-、-NRSO₂NH-、-NHSO₂NR-、-NRSO₂NR-, -SO-or-SO₂-; wherein

Q is optionally substituted with 1-3 independent R^QAnd (3) substitution:

R^Xeach independently selected from-R', halogen, -NO₂、-CN、-OR′、-SR′、-N(R′)₂、-NR′C(O)R′、-NR′C(O)N(R′)₂、-NR′CO₂R′、-C(O)R′、-CO₂R′、-OC(O)R′、-C(O)N(R′)₂、-OC(O)N(R′)₂、-SOR′、-SO₂R′、-SO₂N(R′)₂、-NR′SO₂R′、-NR′SO₂N(R′)₂、-C(O)C(O)R′、-C(O)CH₂C(O)R′、-OP(O)(OR′)₂、-P(O)(OR′)₂、-PO(OR′)(R′)、-P(O)(R′)₂or-OP (O) (R')₂；

Each R is independently selected from hydrogen or C_1-6An aliphatic group optionally substituted with 1-3 independent substituents selected from the group consisting of: -R^T、-T-Ar¹Halogen, oxo, thio, -OR^T、-SR^T、-N(R^T)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R^T、-COR^T、-CON(R^T)₂、-OCOR^T、-NR^TCOR^T、-SO₂R^T、-SO₂N(R^T)₂or-NR^TSO₂R^T(ii) a Wherein

Each R^TIndependently is hydrogen or unsubstituted C_1-6An aliphatic group; or

In the same substituentOr any two R on different substituents^TThe groups together with the atoms to which each group is attached optionally form a 3-8 membered saturated or partially unsaturated monocyclic, or 5-6 membered monocyclic aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein said monocyclic ring is optionally substituted with 1-3 independent substituents selected from the group consisting of: -R^R、-T-Ar¹Halogen, oxo, thio, -OR^R、-SR^R、-N(R^R)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R^R、-COR^R、-CON(R^R)₂、-OCOR^R、-NR^RCOR^R、-SO₂R^R、-SO₂N(R^R)₂or-NR^RSO₂R^R(ii) a Wherein

Each R^RIndependently is hydrogen or unsubstituted C_1-6An aliphatic group;

t is (CH)₂)_w；

w is 0 to 2;

Ar¹selected from a 3-8 membered saturated or partially unsaturated ring, a 5-6 membered aromatic ring, a 3-7 membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein

Ar¹Optionally substituted with 1-3 independent substituents: -R^WOxo, thio, -CO₂R^W、-OR^W、-N(R^W)₂、-SR^W、-NO₂Halogen, -CN, -C_1-4Haloalkyl, -C_1-4Haloalkoxy, -C (O) N (R)^W)₂、-NR^WC(O)R^W、-SO₂R^W、-SO₂N(R^W)₂、-NR^WSO₂R^W、-NR^WCON(R^W)₂、-NR^WCO₂R^W、-COR^W、-OCOR^W、-OCON(R^W)₂、-SOR^W、-NR^WSO₂N(R^W)₂、-COCOR^W、-COCH₂COR^W、-OP(O)(OR^W)₂、-P(O)(OR^W)₂、-PO(OR^W)(R^W)、-P(O)(R^W)₂or-OP (O) (R)^W)₂(ii) a Wherein

R^WIs hydrogen or unsubstituted C_1-6An aliphatic group;

R^Qselected from halogen, -R^S、-N(R^S)₂、-SR^S、-OR^S、C_3-10Alicyclic group, C_6-10Aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, oxo, thioxo, -C_1-4Haloalkoxy, -C_1-4Haloalkyl, -NO₂、-CN、-CF₃、-OCF₃、-CO₂R^S、-COR^S、-OC(O)R^Sor-NR^SC(O)R^S(ii) a Wherein

R^SIs hydrogen or unsubstituted C_1-6An aliphatic group; or

Any two R on the same substituent or different substituents^QOr two R^SA group, or R^QGroup and R^SAny combination of groups, together with one or more atoms to which each group is attached, optionally form a 3-8 membered saturated or partially unsaturated monocyclic, or 5-6 membered monocyclic aromatic ring; each ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein any of said monocyclic rings is optionally substituted with 1-3 independent substituents selected from the group consisting of: r⁰Halogen, oxo, thio, -OR⁰、-SR⁰、-N(R⁰)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R⁰、-COR⁰、-CON(R⁰)₂、-OCOR⁰、-NR⁰COR⁰、-SO₂R⁰、-SO₂N(R⁰)₂or-NR⁰SO₂R⁰(ii) a Wherein

R⁰Is hydrogen or unsubstituted C_1-6An aliphatic group;

r' is independently selected from hydrogen or C_1-8Aliphatic radical, C_6-10Aryl, heteroaryl ring having 5-10 ring atoms, or heterocyclic ring having 3-10 ring atoms, or wherein R and R 'together with the atom or atoms to which they are attached, or 2R' together with the atoms to which they are attached, form a 5-8 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein said C_1-8Aliphatic radical, C_6-10The aryl, heteroaryl ring or heterocycle is optionally substituted with 1-3 independent substituents selected from the group consisting of: r^IHalogen, oxo, thio, -OR^I、-SR^I、-N(R^I)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R^I、-COR^I、-CONHR^I、-OCOR^I、-NR^ICOR^I、-SO₂R^I、-SO₂N(R^I)₂or-NR^ISO₂R^I(ii) a Wherein

R^IIs hydrogen or unsubstituted C_1-6An aliphatic group; but instead of the other end of the tube

With the proviso that the following compounds are excluded:

3- (4-chloro-3-methyl-isoxazol-5-ylaminosulfonyl) -thiophene-2-carboxylic acid (3-methanesulfonylamino-2, 4, 6-trimethyl-phenyl) -amide [ and the trifluoroacetate salt of 1 ];

2.2-methyl-pyridine-3, 5-dicarboxylic acid 5- [ (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -amide ]3- { [4- (pyridin-2-ylmethoxy) -phenyl ] -amide };

3.2-methyl-pyridine-3, 5-dicarboxylic acid 5- [ (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -amide ]3- { [4- (pyridin-4-ylmethoxy) -phenyl ] -amide };

2- (4-fluoro-benzylamino) -N- (3-methanesulfonylamino-5-trifluoromethyl-phenyl) -nicotinamide;

n- (3-methanesulfonylamino-5-trifluoromethyl-phenyl) -2- [ (2-methylamino-pyrimidin-4-ylmethyl) -amino ] -nicotinamide;

n- (3-methanesulfonylamino-5-trifluoromethyl-phenyl) -2- [ (pyridin-4-ylmethyl) -amino ] -nicotinamide;

7.5-chloro-pyridine-2-carboxylic acid { 5-methanesulfonylamino-2- [4- (2-oxo-piperidin-1-yl) -phenylcarbamoyl ] -phenyl } -amide;

3- (4-chloro-3-methyl-isoxazol-5-ylaminosulfonyl) -thiophene-2-carboxylic acid (3-methanesulfonylamino-2, 4, 6-trimethyl-phenyl) -amide;

3, 5-pyridinedicarboxamide, N5- [5- (1, 1-dimethylethyl) -2-methoxy-3- [ (methylsulfonyl) amino ] phenyl ] -2-methyl-N3- [4- (2-pyridylmethoxy) phenyl ] -;

3, 5-pyridinedicarboxamide, N5- [5- (1, 1-dimethylethyl) -2-methoxy-3- [ (methylsulfonyl) amino ] phenyl ] -2-methyl-N3- [4- (4-pyridylmethoxy) phenyl ] -;

11.2-Furancarboxamide, N- [3- [ (methylsulfonyl) amino ] phenyl ] -N- [1- (2-phenylethyl) -4-piperidinyl ] -, ethanedioic acid salt (1: 1);

2-furancarboxamide, N- [3- [ (methylsulfonyl) amino ] phenyl ] -N- [1- (2-phenylethyl) -4-piperidinyl ] -;

1H-pyrrole-3-carboxamide, 2, 5-dimethyl-N- [3- [ (methylsulfonyl) amino ] phenyl ] -1- [2- (trifluoromethyl) phenyl ] -;

4-thiazolecarboxamide, N- [3- [ (methylsulfonyl) amino ] phenyl ] -2- [ [3- (4-morpholinyl) propyl ] (2-thienylcarbonyl) amino ] -;

3-pyridinecarboxamide, N- [3- [ (methylsulfonyl) amino ] phenyl ] -2- [ (4-pyridylmethyl) thio ] -;

3-furancarboxamide, N- [4- [2- [ (1-methylethyl) amino ] ethoxy ] -3- [ (methylsulfonyl) amino ] phenyl ] -;

3-thiophenecarboxamide, N- [ 4-methyl-3- [ (methylsulfonyl) amino ] phenyl ] -;

4-isoxazolecarboxamide, 5-methyl-N- [ 4-methyl-3- [ (methylsulfonyl) amino ] phenyl ] -3-phenyl-;

1, 2, 3-thiadiazole-5-carboxamide, 4-methyl-N- [ 4-methyl-3- [ (methylsulfonyl) amino ] phenyl ] -;

4-isoxazolecarboxamide, 3, 5-dimethyl-N- [ 4-methyl-3- [ (methylsulfonyl) amino ] phenyl ];

2-furancarboxamide, N- [3- [ methyl (methylsulfonyl) amino ] phenyl ] -;

3-pyridinecarboxamide, N- [3- [ (methylsulfonyl) amino ] -5- (trifluoromethyl) phenyl ] -2- [ (4-pyridylmethyl) amino ] -;

3-pyridinecarboxamide, 2- [ [ [2- (methylamino) -4-pyridinyl ] methyl ] amino ] -N- [3- [ (methylsulfonyl) amino ] -5- (trifluoromethyl) phenyl ] -;

3-pyridinecarboxamide, 2- [ [ [2- (methylamino) -4-pyrimidinyl ] methyl ] amino ] -N- [3- [ (methylsulfonyl) amino ] -5- (trifluoromethyl) phenyl ] -;

3-pyridinecarboxamide, 2- [ [ (2-methoxy-4-pyridinyl) methyl ] amino ] -N- [3- [ (methylsulfonyl) amino ] -5- (trifluoromethyl) phenyl ];

3-pyridinecarboxamide, 2- (1H-indazol-6-ylamino) -N- [3- [ (methylsulfonyl) amino ] -5- (trifluoromethyl) phenyl ] -;

2-thiophenecarboxamide, N- [ 4-methyl-3- [ (methylsulfonyl) amino ] phenyl ] -;

3-pyridinecarboxamide, 2- [ [ (4-fluorophenyl) methyl ] amino ] -N- [3- [ (methylsulfonyl) amino ] -5- (trifluoromethyl) phenyl ] -;

1H-pyrazole-4-carboxamide, 1- (4-chlorophenyl) -N- [3- [ (methylsulfonyl) amino ] phenyl ] -5- (trifluoromethyl) -;

2-pyridinecarboxamide, 5-chloro-N- [5- [ (methylsulfonyl) amino ] -2- [ [ [4- (2-oxo-1-piperidinyl) phenyl ] amino ] carbonyl ] phenyl ] -;

3- [ [ (3, 4-dimethyl-5-isoxazolyl) amino ] sulfonyl ] -N- [2, 4, 6-trimethyl-3- [ (methylsulfonyl) amino ] phenyl ] -;

2-thiophenecarboxamide, 3- (4-chloro-3-methyl-5-isoxazolyl) -N- [2, 4, 6-trimethyl-3- [ (methylsulfonyl) amino ] phenyl ] -;

2-thiophenecarboxamide, 3- [ [ (4, 5-dimethyl-3-isoxazolyl) amino ] sulfonyl ] -N- [2, 4, 6-trimethyl-3- [ (methylsulfonyl) amino ] phenyl ] -;

2-thiophenecarboxamide, 3- [ [ (3-methoxypyrazinyl) amino ] sulfonyl ] -N- [2, 4, 6-trimethyl-3- [ (methylsulfonyl) amino ] phenyl ] -, monosodium salt;

2-thiophenecarboxamide, 3- [ (2, 1, 3-benzothiadiazol-5-ylamino) sulfonyl ] -N- [2, 4, 6-trimethyl-3- [ (methylsulfonyl) amino ] phenyl ] -, monosodium salt;

2-thiophenecarboxamide, 3- [ [ (4, 5-dimethyl-3-isoxazolyl) amino ] sulfonyl ] -N- [2, 4, 6-trimethyl-3- [ (methylsulfonyl) amino ] phenyl ] -, monosodium salt;

2-thiophenecarboxamide, 3- [ [ (4-chloro-3-methyl-5-isoxazolyl) amino ] sulfonyl ] -N- [2, 4, 6-trimethyl-3- [ (methylsulfonyl) amino ] phenyl ] -, monosodium salt;

3-furancarboxamide, N- [4- [2- [ (1-methylethyl) amino ] ethoxy ] -3- [ (methylsulfonyl) amino ] phenyl ] -, monohydrochloride;

2-thiophenecarboxamide, 3- [ [ (3-methoxy-2-pyrazinyl) amino ] sulfonyl ] -N- [2, 4, 6-trimethyl-3- [ (methylsulfonyl) amino ] phenyl ] -;

2-thiophenecarboxamide, 3- [ (2, 1, 3-benzothiadiazol-5-ylamino) sulfonyl ] -N- [2, 4, 6-trimethyl-3- [ (methylsulfonyl) amino ] phenyl ] -;

2-thiophenecarboxamide, 3- [ [ (3, 4-dimethyl-5-isoxazolyl) amino ] sulfonyl ] -N- [2, 4, 6-trimethyl-3- [ (methylsulfonyl) amino ] phenyl ] -, monosodium salt;

2-thiophenecarboxamide, 3- [ [ (4-chloro-5-methyl-3-isoxazolyl) amino ] sulfonyl ] -N- [2, 4, 6-trimethyl-3- [ (methylsulfonyl) amino ] phenyl ] -; and

43.1H-pyrazole-3-carboxamide, N- [3- [ (butylsulfonyl) amino ] phenyl ] -4- [ (3-ethyl-4, 5-dimethyl-2 (3H) -oxazolylidene) ethylidene ] -4, 5-dihydro-5-oxo-1- (tetrahydro-1, 1-dioxo-3-thienyl) -.

In another embodiment, the present invention provides a compound of formula I ″:

or a pharmaceutically acceptable salt thereof, wherein:

ring B is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein ring B is optionally substituted with up to x R³Substitution;

X¹、X²、X³and X⁴Each independently is nitrogen or C-R⁴Provided that X is¹、X²、X³And X⁴Is not nitrogen at the same time;

each R²Independently hydrogen, or C_1-6Aliphatic radical in which up to 2 carbon atoms, other than the atom bound to the nitrogen atom, are optionally O, S, NR^NOr C (O) instead;

x is 0 to 4;

R^Neach independently selected from hydrogen or C_1-6An aliphatic group optionally substituted with 1-3 independent substituents selected from the group consisting of: -R^JOxo, thio, -CO₂R^J、-OR^J、-N(R^J)₂、-SR^J、-NO₂Halogen, -CN, -C_1-4Haloalkyl, -C_1-4Haloalkoxy, -C (O) N (R)^J)₂、-NR^JC(O)R^J、-SO₂R^J、-SO₂N(R^J)₂、-NR^JSO₂R^J、-NR^JCON(R^J)₂、-NR^JCO₂R^J、-COR^J、-OCOR^J、-OCON(R^J)₂、-SOR^J、-NR^JSO₂N(R^J)₂、-COCOR^J、-COCH₂COR^J、-OP(O)(OR^J)₂、-P(O)(OR^J)₂、-PO(OR^J)(R^J)、-P(O)(R^J)₂or-OP (O) (R)^J)₂(ii) a Wherein

R^JIs hydrogen or unsubstituted C_1-6An aliphatic group;

R³and R⁴Each independently is Q-R^X；

Q is a bond or C_1-6An aliphatic chain in which up to 3 methylene units of Q are optionally and independently replaced by: -NH-, -NR-, -O-, -S-, -CO-, -C₂-、-OC(O)-、-C(O)CO-、-C(O)-、-C(S)-、-C(O)NH-、-C(O)NR-、-C(＝N-CN)-、-NHCO-、-NRCO-、-NHC(O)O-、-NRC(O)O-、-SO₂NH-、-SO₂NR-、-NHSO₂-、-NRSO₂-、-NHC(O)NH-、-NRC(O)NH-、-NHC(O)NR-、-NRC(O)NR、-OC(O)NH-、-OC(O)NR-、-NHSO₂NH-、-NRSO₂NH-、-NHSO₂NR-、-NRSO₂NR-, -SO-or-SO₂-; wherein

Q is optionally substituted with 1-3 independent R^QAnd (3) substitution:

R^Xeach independently selected from-R', halogen, -NO₂、-CN、-OR′、-SR′、-N(R′)₂、-NR′C(O)R′、-NR′C(O)N(R′)₂、-NR′CO₂R′、-C(O)R′、-CO₂R′、-OC(O)R′、-C(O)N(R′)₂、-OC(O)N(R′)₂、-SOR′、-SO₂R′、-SO₂N(R′)₂、-NR′SO₂R′、-NR′SO₂N(R′)₂、-C(O)C(O)R′、-C(O)CH₂C(O)R′、-OP(O)(OR′)₂、-P(O)(OR′)₂、-PO(OR′)(R′)、-P(O)(R′)₂or-OP (O) (R')₂；

Each R is independently selected from hydrogen or C_1-6An aliphatic group optionally substituted with 1-3 independent substituents selected from the group consisting of: -R^T、-T-Ar¹Halogen, oxo, thio, -OR^T、-SR^T、-N(R^T)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R^T、-COR^T、-CON(R^T)₂、-OCOR^T、-NR^TCOR^T、-SO₂R^T、-SO₂N(R^T)₂or-NR^TSO₂R^T(ii) a Wherein

Each R^TIndependently is hydrogen or unsubstituted C_1-6An aliphatic group; or

Any two R on the same substituent or different substituents^TThe groups together with the atoms to which each group is attached optionally form a 3-8 membered saturated or partially unsaturated monocyclic, or 5-6 membered monocyclic aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein said monocyclic ring is optionally substituted with 1-3 independent substituents selected from the group consisting of: -R^R、-T-Ar¹Halogen, oxo, thio, -OR^R、-SR^R、-N(R^R)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R^R、-COR^R、-CON(R^R)₂、-OCOR^R、-NR^RCOR^R、-SO₂R^R、-SO₂N(R^R)₂or-NR^RSO₂R^R(ii) a Wherein

Each R^RIndependently is hydrogen or unsubstituted C_1-6An aliphatic group;

t is (CH)₂)_w；

w is 0 to 2;

Ar¹selected from a 3-8 membered saturated or partially unsaturated ring, a 5-6 membered aromatic ring, a 3-7 membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein

Ar¹Optionally substituted with 1-3 independent substituents: -R^WOxo, thio, -CO₂R^W、-OR^W、-N(R^W)₂、-SR^W、-NO₂Halogen, -CN, -C_1-4Haloalkyl, -C_1-4Haloalkoxy, -C (O) N (R)^W)₂、-NR^WC(O)R^W、-SO₂R^W、-SO₂N(R^W)₂、-NR^WSO₂R^W、-NR^WCON(R^W)₂、-NR^WCO₂R^W、-COR^W、-OCOR^W、-OCON(R^W)₂、-SOR^W、-NR^WSO₂N(R^W)₂、-COCOR^W、-COCH₂COR^W、-OP(O)(OR^W)₂、-P(O)(OR^W)₂、-PO(OR^W)(R^W)、-P(O)(R^W)₂or-OP (O) (R)^W)₂(ii) a Wherein

R^WIs hydrogen or unsubstituted C_1-6An aliphatic group;

R^Qselected from halogen, -R^S、-N(R^S)₂、-SR^S、-OR^S、C_3-10Alicyclic group, C_6-10Aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, oxo, thioxo, -C_1-4Haloalkoxy, -C_1-4Haloalkyl, -NO₂、-CN、-CF₃、-OCF₃、-CO₂R^S、-COR^S、-OC(O)R^Sor-NR^SC(O)R^S(ii) a Wherein

R^SIs hydrogen or unsubstituted C_1-6An aliphatic group; or

Any two R on the same substituent or different substituents^QOr two R^SA group, or R^QGroup and R^SAny combination of groups, together with one or more atoms to which each group is attached, optionally form a 3-8 membered saturated or partially unsaturated monocyclic, or 5-6 membered monocyclic aromatic ring; each ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein any of said monocyclic rings is optionally substituted with 1-3 independent substituents selected from the group consisting of: r⁰Halogen, oxo, thio, -OR⁰、-SR⁰、-N(R⁰)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R⁰、-COR⁰、-CON(R⁰)₂、-OCOR⁰、-NR⁰COR⁰、-SO₂R⁰、-SO₂N(R⁰)₂or-NR⁰SO₂R⁰(ii) a Wherein

R⁰Is hydrogen or unsubstituted C_1-6An aliphatic group;

r' is independently selected from hydrogen or C_1-8Aliphatic radical, C_6-10Aryl, heteroaromatic rings having 5 to 10 ring atoms, orA heterocyclic ring having 3 to 10 ring atoms, or wherein R and R 'together with one or more atoms to which they are attached, or 2R' together with atoms to which they are attached, form a 5-8 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein said C_1-8Aliphatic radical, C_6-10The aryl, heteroaryl ring or heterocycle is optionally substituted with 1-3 independent substituents selected from the group consisting of: r^IHalogen, oxo, thio, -OR^I、-SR^I、-N(R^I)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R^I、-COR^I、-CONHR^I、-OCOR^I、-NR^ICOR^I、-SO₂R^I、-SO₂N(R^I)₂or-NR^ISO₂R^I(ii) a Wherein

R^IIs hydrogen or unsubstituted C_1-6An aliphatic group.

In some embodiments of the compounds of formula I, I' or I ", ring B is an optionally substituted 6-membered heteroaryl ring.

In some embodiments of the compounds of formula I, I' or I ", ring B is selected from:

in some embodiments of the compounds of formula I, I' or I ", ring B is an optionally substituted 5-membered heteroaryl ring.

In some embodiments of the compounds of formula I, I' or I ", ring B is selected from:

in some embodiments of the compounds of formula I, I' or I ", ring B is selected from:

in other embodiments of the compounds of formula I, I 'or I', ring B is selected from:

in other embodiments of the compounds of formula I, I 'or I', ring B is selected from:

in other embodiments of the compounds of formula I, I 'or I', ring B is selected from:

in some embodiments of the compounds of formula I, I 'or I', x is 1-3.

In some embodiments of the compounds of formula I, I 'or I', x is 1-3, and each R is³Independently selected from hydrogen, halogen, CN, CF₃、NO₂Or optionally substituted groups selected from: c_1-6Aliphatic radical, C_1-6Alicyclic group, C_6-10Aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, arylalkyl, -N (R')₂、-CH₂N(R′)₂、-OR′、-CH₂OR′、-SR′、-CH₂SR′、-C(O)R′、-COOR′、-NRCOR′、-CON(R′)₂、-S(O)₂R', or-S (O)₂N(R′)₂。

In some embodiments of the compounds of formula I, I 'or I', x is 1-2, and each R is³Is methyl, ethyl, propyl, isopropyl, tert-butyl, sec-butyl or an optionally substituted group selected from: c_1-6Aliphatic radical, C_6-10Aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl or aralkyl.

In some embodiments of the compounds of formula I or I', the groups

Selected from:

in other embodiments of the compounds of formula I or I', the groups

In some embodiments of the compounds of formula I', the group

Selected from:

in other embodiments of the compounds of formula I or I', the groups

In other embodiments of the compounds of formula I or I', the groups

In other embodiments of the compounds of formula I or I', the groups

In other embodiments of the compounds of formula I', groups

In other embodiments of the compounds of formula I', groups

In other embodiments of the compounds of formula I or I', the groups

In some embodiments of the compounds of formula I or I', the groups

Selected from the group consisting of rings a-1, a-2 or a-3.

In some embodiments of the compounds of formula I, I 'or I', when present, each R⁴Is hydrogen.

In other embodiments of the compounds of formula I, I 'or I', when present, each R⁴Independently selected from hydrogen, halogen, CN, NO₂Or optionally substituted groups selected from: c_1-6Aliphatic, aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, aralkyl, -N (R')₂、-CH₂N(R′)₂、-OR′、-CH₂OR′、-SR′、-CH₂SR′、-C(O)R′、-COOR′、-NR′COR′、-CON(R′)₂or-S (O)₂N(R′)₂。

In some embodiments of compounds of formula I, R^ASelected from SO₂N(R²)₂Or SO₂R¹. In other embodiments of the compounds of formula I, R^AIs SO₂R¹And R is¹Is C_1-6An alkyl group.

In some embodiments of compounds of formula I', R^AIs SO₂N(R²)₂And two R are²Are all hydrogen.

In other embodiments of the compounds of formula I', at SO₂N(R²)₂In two, R²Are all hydrogen.

In other embodiments of the invention, the compounds have the structure of formula II-A1, II-A2, or II-A3:

or a pharmaceutically acceptable salt thereof, wherein x, R³、R⁴、R^N、R^AAnd ring B is as defined herein for compounds of formula I.

In other embodiments of the invention, the compounds have the structure of formula II ' -A1, II ' -A2, or II ' -A3:

or a pharmaceutically acceptable salt thereof, wherein x, R³、R⁴、R^N、R^AAnd ring B is as defined herein for compounds of formula I'.

In other embodiments of the invention, the compounds have the structure of formula II "-A1, II" -A2, or II "-A3:

or a pharmaceutically acceptable salt thereof, wherein x, R³、R⁴、R^NAnd ring B is as defined herein for the compound of formula I'.

In other embodiments of the invention, the compound has the structure of formula II "-A4:

or a pharmaceutically acceptable salt thereof, wherein x, R³、R⁴、R^NAnd ring B is as defined herein for the compound of formula I'.

In some embodiments of compounds of formula II-A1, II-A2, II-A3, II ' -A1, II ' -A2, II ' -A3, II "-A1, II" -A2, II "-A3, or II" -A4, ring B is an optionally substituted 6-membered heteroaryl ring.

In some embodiments of compounds of formula II-A1, II-A2, II-A3, II ' -A1, II ' -A2, II ' -A3, II "-A1, II" -A2, II "-A3, or II" -A4, ring B is selected from:

in some embodiments of compounds of formula II-A1, II-A2, II-A3, II ' -A1, II ' -A2, II ' -A3, II "-A1, II" -A2, II "-A3, or II" -A4, ring B is an optionally substituted 5-membered heteroaryl ring.

In some embodiments of compounds of formula II-A1, II-A2, II-A3, II ' -A1, II ' -A2, II ' -A3, II "-A1, II" -A2, II "-A3, or II" -A4, ring B is selected from:

in some embodiments of compounds of formula II-A1, II-A2, II-A3, II ' -A1, II ' -A2, II ' -A3, II "-A1, II" -A2, II "-A3, or II" -A4, ring B is selected from:

in other embodiments of the compounds of formula II-A1, II-A2, II-A3, II ' -A1, II ' -A2, II ' -A3, II "-A1, II" -A2, II "-A3, or II" -A4, ring B is selected from:

in other embodiments of the compounds of formula II-A1, II-A2, II-A3, II ' -A1, II ' -A2, II ' -A3, II "-A1, II" -A2, II "-A3, or II" -A4, ring B is selected from:

in some embodiments of the compounds of formula II-A1, II-A2, II-A3, II ' -A1, II ' -A2, II ' -A3, II "-A1, II" -A2, II "-A3, or II" -A4, x is 1-3. In other embodiments, x is 1 to 3, and each R³Independently selected from hydrogen, halogen, CN, CF₃、NO₂Or optionally substituted groups selected from: c_1-6Aliphatic radical, C_1-6Alicyclic group, C_6-10Aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, arylalkyl, -N (R')₂、-CH₂N(R′)₂、-OR′、-CH₂OR′、-SR′、-CH₂SR′、-C(O)R′、-COOR′、-NRCOR′、-CON(R′)₂、-S(O)₂R', or-S (O)₂N(R′)₂. In other embodiments, x is 1-2, and each R³Is methyl, ethylPropyl, isopropyl, tert-butyl, sec-butyl or optionally substituted group selected from: c_1-6Aliphatic radical, C_6-10Aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl or aralkyl.

In some embodiments of compounds of formula II-A1, II-A2, II-A3, II ' -A1, II ' -A2, II ' -A3, II "-A1, II" -A2, II "-A3, or II" -A4, each R⁴And, when present, is hydrogen. In other embodiments, each R is⁴When present, is independently selected from hydrogen, halogen, CN, NO₂Or optionally substituted groups selected from: c_1-6Aliphatic, aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, aralkyl, -N (R')₂、-CH₂N(R′)₂、-OR′、-CH₂OR′、-SR′、-CH₂SR′、-C(O)R′、-COOR′、-NR′COR′、-CON(R′)₂or-S (O)₂N(R′)₂。

In some embodiments of the compounds of formula II-A1, II-A2, or II-A3, R^ASelected from SO₂N(R²)₂Or SO₂R¹。

In some embodiments of the compounds of formula II-A1, II-A2, or II-A3, R^AIs SO₂N(R²)₂And two R are²Are all hydrogen.

In some embodiments of the compounds of formula II-A1, II-A2, or II-A3, R^AIs SO₂R¹And R is¹Is C_1-6An alkyl group.

In some embodiments of the compounds of formulae II ' -A1, II ' -A2, II ' -A3, R^AIs SO₂N(R²)₂And two R are²Are all hydrogen.

In some embodiments of the compounds of formula II' -A4, in SO²N(R²)₂In two, R²Are all hydrogen.

In some embodiments, the present invention provides a method of modulating a sodium channel, the method comprising the steps of: contacting the channel with a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

ring B is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein ring B is optionally substituted with up to x R³Substitution;

X¹、X²、X³and X⁴Each independently is nitrogen or C-R⁴Provided that X is¹、X²、X³And X⁴Is not nitrogen at the same time;

R^Aselected from SO₂N(R²)₂、SO₂R¹、NR²SO₂R¹；

R¹Is C_1-6Aliphatic radical in which up to 2 atoms other than the atom bound to the nitrogen or oxygen atom are optionally O, S, NR^NOr C (O) instead;

each R²Independently hydrogen, or C_1-6Aliphatic radical in which up to 2 carbon atoms, other than the atom bound to the nitrogen atom, are optionally O, S, NR^NOr C (O) instead;

x is 0 to 4;

R^Neach independently selected from hydrogen or C_1-6An aliphatic group optionally substituted with 1-3 independent substituents selected from the group consisting of: -R^JOxo, thio, -CO₂R^J、-OR^J、-N(R^J)₂、-SR^J、-NO₂Halogen, -CN, -C_1-4Haloalkyl, -C_1-4Haloalkoxy, -C (O) N (R)^J)₂、-NR^JC(O)R^J、-SO₂R^J、-SO₂N(R^J)₂、-NR^JSO₂R^J、-NR^JCON(R^J)₂、-NR^JCO₂R^J、-COR^J、-OCOR^J、-OCON(R^J)₂、-SOR^J、-NR^JSO₂N(R^J)₂、-COCOR^J、-COCH₂COR^J、-OP(O)(OR^J)₂、-P(O)(OR^J)₂、-PO(OR^J)(R^J)、-P(O)(R^J)₂or-OP (O) (R)^J)₂(ii) a Wherein

R^JIs hydrogen or unsubstituted C_1-6An aliphatic group;

R³and R⁴Each independently is Q-R^X；

Q is a bond or C_1-6An aliphatic chain in which up to 3 methylene units of Q are optionally and independently replaced by: -NH-, -NR-, -O-, -S-, -CO-, -C₂-、-OC(O)-、-C(O)CO-、-C(O)-、-C(S)-、-C(O)NH-、-C(O)NR-、-C(＝N-CN)-、-NHCO-、-NRCO-、-NHC(O)O-、-NRC(O)O-、-SO₂NH-、-SO₂NR-、-NHSO₂-、-NRSO₂-、-NHC(O)NH-、-NRC(O)NH-、-NHC(O)NR-、-NRC(O)NR、-OC(O)NH-、-OC(O)NR-、-NHSO₂NH-、-NRSO₂NH-、-NHSO₂NR-、-NRSO₂NR-, -SO-or-SO₂-; wherein

Q is optionally substituted with 1-3 independent R^QAnd (3) substitution:

R^Xeach independently selected from-R', halogen, -NO₂、-CN、-OR′、-SR′、-N(R′)₂、-NR′C(O)R′、-NR′C(O)N(R′)₂、-NR′CO₂R′、-C(O)R′、-CO₂R′、-OC(O)R′、-C(O)N(R′)₂、-OC(O)N(R′)₂、-SOR′、-SO₂R′、-SO₂N(R′)₂、-NR′SO₂R′、-NR′SO₂N(R′)₂、-C(O)C(O)R′、-C(O)CH₂C(O)R′、-OP(O)(OR′)₂、-P(O)(OR′)₂、-PO(OR′)(R′)、-P(O)(R′)₂or-OP (O) (R')₂；

Each R is independently selected from hydrogen or C_1-6An aliphatic group optionally substituted with 1-3 independent substituents selected from the group consisting of: -R^T、-T-Ar¹Halogen, oxo, thio, -OR^T、-SR^T、-N(R^T)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R^T、-COR^T、-CON(R^T)₂、-OCOR^T、-NR^TCOR^T、-SO₂R^T、-SO₂N(R^T)₂or-NR^TSO₂R^T(ii) a Wherein

Each R^TIndependently is hydrogen or unsubstituted C_1-6An aliphatic group; or

Any two R on the same substituent or different substituents^TThe groups together with the atoms to which each group is attached optionally form a 3-8 membered saturated or partially unsaturated monocyclic, or 5-6 membered monocyclic aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein said monocyclic ring is optionally substituted with 1-3 independent substituents selected from the group consisting of: -R^R、-T-Ar¹Halogen, oxo, thio, -OR^R、-SR^R、-N(R^R)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R^R、-COR^R、-CON(R^R)₂、-OCOR^R、-NR^RCOR^R、-SO₂R^R、-SO₂N(R^R)₂or-NR^RSO₂R^R(ii) a Wherein

Each R^RIndependently is hydrogen or unsubstituted C_1-6An aliphatic group;

t is (CH)₂)_w；

w is 0 to 2;

Ar¹selected from a 3-8 membered saturated or partially unsaturated ring, a 5-6 membered aromatic ring, a 3-7 membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein

Ar¹Optionally substituted with 1-3 independent substituents: -R^WOxo, thio, -CO₂R^W、-OR^W、-N(R^W)₂、-SR^W、-NO₂Halogen, -CN, -C_1-4Haloalkyl, -C_1-4Haloalkoxy, -C (O) N (R)^W)₂、-NR^WC(O)R^W、-SO₂R^W、-SO₂N(R^W)₂、-NR^WSO₂R^W、-NR^WCON(R^W)₂、-NR^WCO₂R^W、-COR^W、-OCOR^W、-OCON(R^W)₂、-SOR^W、-NR^WSO₂N(R^W)₂、-COCOR^W、-COCH₂COR^W、-OP(O)(OR^W)₂、-P(O)(OR^W)₂、-PO(OR^W)(R^W)、-P(O)(R^W)₂or-OP (O) (R)^W)₂(ii) a Wherein

R^WIs hydrogen or unsubstituted C_1-6An aliphatic group;

R^Qselected from halogen, -R^S、-N(R^S)₂、-SR^S、-OR^S、C_3-10Alicyclic group, C_6-10Aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, oxo, thioxo, -C_1-4Haloalkoxy, -C_1-4Haloalkyl, -NO₂、-CN、-CF₃、-OCF₃、-CO₂R^S、-COR^S、-OC(O)R^Sor-NR^SC(O)R^S(ii) a Wherein

R^SIs hydrogen or unsubstituted C_1-6An aliphatic group; or

Any two R on the same substituent or different substituents^QOr two R^SA group, or R^QGroup and R^SAny combination of groups, together with one or more atoms to which each group is attached, optionally form a 3-8 membered saturated or partially unsaturated monocyclic, or 5-6 membered monocyclic aromatic ring; each ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein any of said monocyclic rings is optionally substituted with 1-3 independent substituents selected from the group consisting of: r⁰Halogen, oxo, thio, -OR⁰、-SR⁰、-N(R⁰)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R⁰、-COR⁰、-CON(R⁰)₂、-OCOR⁰、-NR⁰COR⁰、-SO₂R⁰、-SO₂N(R⁰)₂or-NR⁰SO₂R⁰(ii) a Wherein

R⁰Is hydrogen or unsubstituted C_1-6An aliphatic group;

r' is independently selected from hydrogen or C_1-8Aliphatic radical, C_6-10Aryl, heteroaryl ring having 5-10 ring atoms, or heterocyclic ring having 3-10 ring atoms, or wherein R and R 'together with the atom or atoms to which they are attached, or 2R' together with the atoms to which they are attached, form a 5-8 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein said C_1-8Aliphatic radical, C_6-10The aryl, heteroaryl ring or heterocycle is optionally substituted with 1-3 independent substituents selected from the group consisting of: r^IHalogen, oxo, thio, -OR^I、-SR^I、-N(R^I)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R^I、-COR^I、-CONHR^I、-OCOR^I、-NR^ICOR^I、-SO₂R^I、-SO₂N(R^I)₂or-NR^ISO₂R^I(ii) a Wherein

R^IIs hydrogen or unsubstituted C_1-6An aliphatic group.

In some embodiments, the present invention provides a method of modulating a sodium channel, the method comprising the steps of: contacting the channel with a compound of formula I':

or a pharmaceutically acceptable salt thereof, wherein:

ring B is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein ring B is optionally substituted with up to x R³Substitution;

X¹、X²、X³and X⁴Each independently is nitrogen or C-R⁴Provided that X is¹、X²、X³And X⁴Is not nitrogen at the same time;

R^Aselected from SO₂N(R²)₂Or NR²SO₂R¹；

R¹Is C_1-6Aliphatic radical in which up to 2 atoms other than the atom bound to the nitrogen or oxygen atom are optionally O, S, NR^NOr C (O) instead;

each R²Independently hydrogen, or C_1-6Aliphatic radical in which up to 2 atoms are present other than the atom bonded to the nitrogen atomCarbon atoms optionally substituted by O, S, NR^NOr C (O) instead;

x is 0 to 4;

R^Neach independently selected from hydrogen or C_1-6An aliphatic group optionally substituted with 1-3 independent substituents selected from the group consisting of: -R^JOxo, thio, -CO₂R^J、-OR^J、-N(R^J)₂、-SR^J、-NO₂Halogen, -CN, -C_1-4Haloalkyl, -C_1-4Haloalkoxy, -C (O) N (R)^J)₂、-NR^JC(O)R^J、-SO₂R^J、-SO₂N(R^J)₂、-NR^JSO₂R^J、-NR^JCON(R^J)₂、-NR^JCO₂R^J、-COR^J、-OCOR^J、-OCON(R^J)₂、-SOR^J、-NR^JSO₂N(R^J)₂、-COCOR^J、-COCH₂COR^J、-OP(O)(OR^J)₂、-P(O)(OR^J)₂、-PO(OR^J)(R^J)、-P(O)(R^J)₂or-OP (O) (R)^J)₂(ii) a Wherein

R^JIs hydrogen or unsubstituted C_1-6An aliphatic group;

R³and R⁴Each independently is Q-R^X；

Q is a bond or C_1-6An aliphatic chain in which up to 3 methylene units of Q are optionally and independently replaced by: -NH-, -NR-, -O-, -S-, -CO-, -C₂-、-OC(O)-、-C(O)CO-、-C(O)-、-C(S)-、-C(O)NH-、-C(O)NR-、-C(＝N-CN)-、-NHCO-、-NRCO-、-NHC(O)O-、-NRC(O)O-、-SO₂NH-、-SO₂NR-、-NHSO₂-、-NRSO₂-、-NHC(O)NH-、-NRC(O)NH-、-NHC(O)NR-、-NRC(O)NR、-OC(O)NH-、-OC(O)NR-、-NHSO₂NH-、-NRSO₂NH-、-NHSO₂NR-、-NRSO₂NR-、-SO-or-SO₂-; wherein

Q is optionally substituted with 1-3 independent R^QAnd (3) substitution:

R^Xeach independently selected from-R', halogen, -NO₂、-CN、-OR′、-SR′、-N(R′)₂、-NR′C(O)R′、-NR′C(O)N(R′)₂、-NR′CO₂R′、-C(O)R′、-CO₂R′、-OC(O)R′、-C(O)N(R′)₂、-OC(O)N(R′)₂、-SOR′、-SO₂R′、-SO₂N(R′)₂、-NR′SO₂R′、-NR′SO₂N(R′)₂、-C(O)C(O)R′、-C(O)CH₂C(O)R′、-OP(O)(OR′)₂、-P(O)(OR′)₂、-PO(OR′)(R′)、-P(O)(R′)₂or-OP (O) (R')₂；

Each R is independently selected from hydrogen or C_1-6An aliphatic group optionally substituted with 1-3 independent substituents selected from the group consisting of: -R^T、-T-Ar¹Halogen, oxo, thio, -OR^T、-SR^T、-N(R^T)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R^T、-COR^T、-CON(R^T)₂、-OCOR^T、-NR^TCOR^T、-SO₂R^T、-SO₂N(R^T)₂or-NR^TSO₂R^T(ii) a Wherein

Each R^TIndependently is hydrogen or unsubstituted C_1-6An aliphatic group; or

Any two R on the same substituent or different substituents^TThe groups together with the atoms to which each group is attached optionally form a 3-8 membered saturated or partially unsaturated monocyclic, or 5-6 membered monocyclic aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein said monocyclic ring is optionally substituted with 1-3 independent substituents selected from the group consisting of: -R^R、-T-Ar¹Halogen, oxo, thio, -OR^R、-SR^R、-N(R^R)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R^R、-COR^R、-CON(R^R)₂、-OCOR^R、-NR^RCOR^R、-SO₂R^R、-SO₂N(R^R)₂or-NR^RSO₂R^R(ii) a Wherein

Each R^RIndependently is hydrogen or unsubstituted C_1-6An aliphatic group;

t is (CH)₂)_w；

w is 0 to 2;

Ar¹selected from a 3-8 membered saturated or partially unsaturated ring, a 5-6 membered aromatic ring, a 3-7 membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein

Ar¹Optionally substituted with 1-3 independent substituents: -R^WOxo, thio, -CO₂R^W、-OR^W、-N(R^W)₂、-SR^W、-NO₂Halogen, -CN, -C_1-4Haloalkyl, -C_1-4Haloalkoxy, -C (O) N (R)^W)₂、-NR^WC(O)R^W、-SO₂R^W、-SO₂N(R^W)₂、-NR^WSO₂R^W、-NR^WCON(R^W)₂、-NR^WCO₂R^W、-COR^W、-OCOR^W、-OCON(R^W)₂、-SOR^W、-NR^WSO₂N(R^W)₂、-COCOR^W、-COCH₂COR^W、-OP(O)(OR^W)₂、-P(O)(OR^W)₂、-PO(OR^W)(R^W)、-P(O)(R^W)₂or-OP (O) (R)^W)₂(ii) a Wherein

R^WIs hydrogen or unsubstituted C_1-6An aliphatic group;

R^Qselected from halogen, -R^S、-N(R^S)₂、-SR^S、-OR^S、C_3-10Alicyclic group, C_6-10Aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, oxo, thioxo, -C_1-4Haloalkoxy, -C_1-4Haloalkyl, -NO₂、-CN、-CF₃、-OCF₃、-CO₂R^S、-COR^S、-OC(O)R^Sor-NR^SC(O)R^S(ii) a Wherein

R^SIs hydrogen or unsubstituted C_1-6An aliphatic group; or

Any two R on the same substituent or different substituents^QOr two R^SA group, or R^QGroup and R^SAny combination of groups, together with one or more atoms to which each group is attached, optionally form a 3-8 membered saturated or partially unsaturated monocyclic, or 5-6 membered monocyclic aromatic ring; each ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein any of said monocyclic rings is optionally substituted with 1-3 independent substituents selected from the group consisting of: r⁰Halogen, oxo, thio, -OR⁰、-SR⁰、-N(R⁰)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R⁰、-COR⁰、-CON(R⁰)₂、-OCOR⁰、-NR⁰COR⁰、-SO₂R⁰、-SO₂N(R⁰)₂or-NR⁰SO₂R⁰(ii) a Wherein

R⁰Is hydrogen or unsubstituted C_1-6An aliphatic group;

r' is independently selected from hydrogen or C_1-8Aliphatic radical、C_6-10Aryl, heteroaryl ring having 5-10 ring atoms, or heterocyclic ring having 3-10 ring atoms, or wherein R and R 'together with the atom or atoms to which they are attached, or 2R' together with the atoms to which they are attached, form a 5-8 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein said C_1-8Aliphatic radical, C_6-10The aryl, heteroaryl ring or heterocycle is optionally substituted with 1-3 independent substituents selected from the group consisting of: r^IHalogen, oxo, thio, -OR^I、-SR^I、-N(R^I)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R^I、-COR^I、-CONHR^I、-OCOR^I、-NR^ICOR^I、-SO₂R^I、-SO₂N(R^I)₂or-NR^ISO₂R^I(ii) a Wherein

R^IIs hydrogen or unsubstituted C_1-6An aliphatic group.

In other embodiments, the present invention provides methods of modulating a sodium channel, comprising the steps of: contacting said channel with a compound of formula I':

or a pharmaceutically acceptable salt thereof, wherein:

ring B is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein ring B is optionally substituted with up to x R³Substitution;

X¹、X²、X³and X⁴Each independently is nitrogen or C-R⁴Provided that X is¹、X²、X³And X⁴Is not nitrogen at the same time;

each R²Independently hydrogen, or C_1-6Aliphatic radical in which up to 2 carbon atoms, other than the atom bound to the nitrogen atom, are optionally O, S, NR^NOr C (O) instead;

x is 0 to 4;

R^Neach independently selected from hydrogen or C_1-6An aliphatic group optionally substituted with 1-3 independent substituents selected from the group consisting of: -R^JOxo, thio, -CO₂R^J、-OR^J、-N(R^J)₂、-SR^J、-NO₂Halogen, -CN, -C_1-4Haloalkyl, -C_1-4Haloalkoxy, -C (O) N (R)^J)₂、-NR^JC(O)R^J、-SO₂R^J、-SO₂N(R^J)₂、-NR^JSO₂R^J、-NR^JCON(R^J)₂、-NR^JCO₂R^J、-COR^J、-OCOR^J、-OCON(R^J)₂、-SOR^J、-NR^JSO₂N(R^J)₂、-COCOR^J、-COCH₂COR^J、-OP(O)(OR^J)₂、-P(O)(OR^J)₂、-PO(OR^J)(R^J)、-P(O)(R^J)₂or-OP (O) (R)^J)₂(ii) a Wherein

R^JIs hydrogen or unsubstituted C_1-6An aliphatic group;

R³and R⁴Each independently is Q-R^X；

Q is a bond or C_1-6An aliphatic chain in which up to 3 methylene units of Q are optionally and independently replaced by: -NH-, -NR-, -O-, -S-, -CO-, -C₂-、-OC(O)-、-C(O)CO-、-C(O)-、-C(S)-、-C(O)NH-、-C(O)NR-、-C(＝N-CN)-、-NHCO-、-NRCO-、-NHC(O)O-、-NRC(O)O-、-SO₂NH-、-SO₂NR-、-NHSO₂-、-NRSO₂-、-NHC(O)NH-、-NRC(O)NH-、-NHC(O)NR-、-NRC(O)NR、-OC(O)NH-、-OC(O)NR-、-NHSO₂NH-、-NRSO₂NH-、-NHSO₂NR-、-NRSO₂NR-, -SO-or-SO₂-; wherein

Q is optionally substituted with 1-3 independent R^QAnd (3) substitution:

R^Xeach independently selected from-R', halogen, -NO₂、-CN、-OR′、-SR′、-N(R′)₂、-NR′C(O)R′、-NR′C(O)N(R′)₂、-NR′CO₂R′、-C(O)R′、-CO₂R′、-OC(O)R′、-C(O)N(R′)₂、-OC(O)N(R′)₂、-SOR′、-SO₂R′、-SO₂N(R′)₂、-NR′SO₂R′、-NR′SO₂N(R′)₂、-C(O)C(O)R′、-C(O)CH₂C(O)R′、-OP(O)(OR′)₂、-P(O)(OR′)₂、-PO(OR′)(R′)、-P(O)(R′)₂or-OP (O) (R')₂；

Each R is independently selected from hydrogen or C_1-6An aliphatic group optionally substituted with 1-3 independent substituents selected from the group consisting of: -R^T、-T-Ar¹Halogen, oxo, thio, -OR^T、-SR^T、-N(R^T)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R^T、-COR^T、-CON(R^T)₂、-OCOR^T、-NR^TCOR^T、-SO₂R^T、-SO₂N(R^T)₂or-NR^TSO₂R^T(ii) a Wherein

Each R^TIndependently is hydrogen or unsubstituted C_1-6An aliphatic group; or

Any two R on the same substituent or different substituents^TThe groups together with the atoms to which each group is attached optionally form a 3-8 membered saturated or partially unsaturated monocyclic, or 5-6 membered monocyclic aromatic ring having 0-3 members independently selected from nitrogen, oxygen, or sulfurA heteroatom of (a); wherein said monocyclic ring is optionally substituted with 1-3 independent substituents selected from the group consisting of: -R^R、-T-Ar¹Halogen, oxo, thio, -OR^R、-SR^R、-N(R^R)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R^R、-COR^R、-CON(R^R)₂、-OCOR^R、-NR^RCOR^R、-SO₂R^R、-SO₂N(R^R)₂or-NR^RSO₂R^R(ii) a Wherein

Each R^RIndependently is hydrogen or unsubstituted C_1-6An aliphatic group;

t is (CH)₂)_w；

w is 0 to 2;

Ar¹selected from a 3-8 membered saturated or partially unsaturated ring, a 5-6 membered aromatic ring, a 3-7 membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein

Ar¹Optionally substituted with 1-3 independent substituents: -R^WOxo, thio, -CO₂R^W、-OR^W、-N(R^W)₂、-SR^W、-NO₂Halogen, -CN, -C_1-4Haloalkyl, -C_1-4Haloalkoxy, -C (O) N (R)^W)₂、-NR^WC(O)R^W、-SO₂R^W、-SO₂N(R^W)₂、-NR^WSO₂R^W、-NR^WCON(R^W)₂、-NR^WCO₂R^W、-COR^W、-OCOR^W、-OCON(R^W)₂、-SOR^W、-NR^WSO₂N(R^W)₂、-COCOR^W、-COCH₂COR^W、-OP(O)(OR^W)₂、-P(O)(OR^W)₂、-PO(OR^W)(R^W)、-P(O)(R^W)₂or-OP (O) (R)^W)₂(ii) a Wherein

R^WIs hydrogen or unsubstituted C_1-6An aliphatic group;

R^Qselected from halogen, -R^S、-N(R^S)₂、-SR^S、-OR^S、C_3-10Alicyclic group, C_6-10Aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, oxo, thioxo, -C_1-4Haloalkoxy, -C_1-4Haloalkyl, -NO₂、-CN、-CF₃、-OCF₃、-CO₂R^S、-COR^S、-OC(O)R^Sor-NR^SC(O)R^S(ii) a Wherein

R^SIs hydrogen or unsubstituted C_1-6An aliphatic group; or

Any two R on the same substituent or different substituents^QOr two R^SA group, or R^QGroup and R^SAny combination of groups, together with one or more atoms to which each group is attached, optionally form a 3-8 membered saturated or partially unsaturated monocyclic, or 5-6 membered monocyclic aromatic ring; each ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein any of said monocyclic rings is optionally substituted with 1-3 independent substituents selected from the group consisting of: r⁰Halogen, oxo, thio, -OR⁰、-SR⁰、-N(R⁰)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R⁰、-COR⁰、-CON(R⁰)₂、-OCOR⁰、-NR⁰COR⁰、-SO₂R⁰、-SO₂N(R⁰)₂or-NR⁰SO₂R⁰(ii) a Wherein

R⁰Is hydrogen or unsubstituted C_1-6An aliphatic group;

r' is independently selected from hydrogen or C_1-8Aliphatic radical, C_6-10Aryl, heteroaryl ring having 5-10 ring atoms, or heterocyclic ring having 3-10 ring atoms, or wherein R and R 'together with the atom or atoms to which they are attached, or 2R' together with the atoms to which they are attached, form a 5-8 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein said C_1-8Aliphatic radical, C_6-10The aryl, heteroaryl ring or heterocycle is optionally substituted with 1-3 independent substituents selected from the group consisting of: r^IHalogen, oxo, thio, -OR^I、-SR^I、-N(R^I)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R^I、-COR^I、-CONHR^I、-OCOR^I、-NR^ICOR^I、-SO₂R^I、-SO₂N(R^I)₂or-NR^ISO₂R^I(ii) a Wherein

R^IIs hydrogen or unsubstituted C_1-6An aliphatic group.

In some embodiments of formula I, I', or I "of the method, ring B is an optionally substituted 6-membered heteroaryl ring.

In some embodiments of formula I, I', or I "of the methods, ring B is selected from:

in some embodiments of formula I, I', or I "of the method, ring B is an optionally substituted 5-membered heteroaryl ring.

In some embodiments of formula I, I', or I "of the methods, ring B is selected from:

in some embodiments of formula I, I', or I "of the methods, ring B is selected from:

in other embodiments of formula I, I ', or I' of the method, ring B is selected from:

in other embodiments of formula I, I ', or I' of the method, ring B is selected from:

in some embodiments of formula I, I ', or I' of the method, x is 1 to 3. In other embodiments, x is 1 to 3, and each R³Independently selected from hydrogen, halogen, CN, CF₃、NO₂Or optionally substituted groups selected from: c_1-6Aliphatic radical, C_1-6Alicyclic group, C_6-10Aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, arylalkyl, -N (R')₂、-CH₂N(R′)₂、-OR′、-CH₂OR′、-SR′、-CH₂SR′、-C(O)R′、-COOR′、-NRCOR′、-CON(R′)₂、-S(O)₂R', or-S (O)₂N(R′)₂。

In some embodiments of formula I, I ', or I' of the process, x is 1-2, and each R is³Is methyl, ethyl, propyl, isopropyl, tert-butyl, sec-butyl or an optionally substituted group selected from: c_1-6Aliphatic radical, C_6-10Aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl or aralkyl.

In some embodiments of formula I or I' of the methods, the group

Selected from:

in other embodiments of the compounds of formula I or I', the groups

In some embodiments of formula I' of the process, the group

Selected from:

in other embodiments of formula I or I' of the process, groups

In other embodiments of formula I or I' of the process, groups

In other embodiments of formula I or I' of the process, the group

In other embodiments of formula I' of the process, the group

In other embodiments of formula I' of the process, the group

In other embodiments of formula I or I' of the process, the group

In some embodiments of formula I, I ', or I' of the method, the group

Selected from the group consisting of rings a-1, a-2 or a-3.

In some embodiments of formula I, I ', or I' of the process, each R⁴And, when present, is hydrogen. In other embodiments, each R is⁴When present, is independently selected from hydrogen, halogen, CN, NO₂Or optionally substituted groups selected from: c_1-6Aliphatic, aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, aralkyl, -N (R')₂、-CH₂N(R′)₂、-OR′、-CH₂OR′、-SR′、-CH₂SR′、-C(O)R′、-COOR′、-NR′COR′、-CON(R′)₂or-S (O)₂N(R′)₂。

In some embodiments of formula I of the methods, R^ASelected from SO₂N(R²)₂Or SO₂R¹。

In some embodiments of formula I or I' of the methods, R^AIs SO₂R¹，R¹Is C_1-6An alkyl group. In other embodiments of formula I or I' of the methods, R^AIs SO₂N(R²)₂And two R are²Are all hydrogen.

In some embodiments of formula I' of the processIn case of SO₂N(R²)₂In two, R²Are all hydrogen.

In other embodiments of the methods of the present invention, the compound has the structure of formula II-A1, II-A2, or II-A3:

or a pharmaceutically acceptable salt thereof, wherein x, R³、R⁴、R^N、R^AAnd ring B is as defined herein for compounds of formula I.

In other embodiments of the methods of the present invention, the compound has the structure of formula II ' -A1, II ' -A2, or II ' -A3:

or a pharmaceutically acceptable salt thereof, wherein x, R³、R⁴、R^N、R^AAnd ring B is as defined herein for compounds of formula I'.

In other embodiments of the methods of the present invention, the compound has the structure of formula II "-A1, II" -A2, or II "-A3:

or a pharmaceutically acceptable salt thereof, wherein x, R³、R⁴、R^NAnd ring B is as defined herein for the compound of formula I'.

In other embodiments of the methods of the present invention, the compound has the structure of formula II "-A4:

or a pharmaceutically acceptable salt thereof, wherein x, R³、R⁴、R^NAnd ring B is as defined herein for the compound of formula I'.

In some embodiments of the methods of the present invention, in the compounds of formula II-A1, II-A2, II-A3, II ' -A1, II ' -A2, II ' -A3, II "-A1, II" -A2, II "-A3, or II" -A4, ring B is an optionally substituted 6-membered heteroaryl ring.

In some embodiments of the methods of the present invention, in the compound of formula II-A1, II-A2, II-A3, II ' -A1, II ' -A2, II ' -A3, II "-A1, II" -A2, II "-A3, or II" -A4, ring B is selected from:

in some embodiments of the methods of the present invention, in the compounds of formula II-A1, II-A2, II-A3, II ' -A1, II ' -A2, II ' -A3, II "-A1, II" -A2, II "-A3, or II" -A4, ring B is an optionally substituted 5-membered heteroaryl ring.

In some embodiments of the methods of the present invention, in the compound of formula II-A1, II-A2, II-A3, II ' -A1, II ' -A2, II ' -A3, II "-A1, II" -A2, II "-A3, or II" -A4, ring B is selected from:

in some embodiments of the methods of the present invention, in the compound of formula II-A1, II-A2, II-A3, II ' -A1, II ' -A2, II ' -A3, II "-A1, II" -A2, II "-A3, or II" -A4, ring B is selected from:

in other embodiments of the process of the present invention, in the compounds of formula II-A1, II-A2, II-A3, II ' -A1, II ' -A2, II ' -A3, II "-A1, II" -A2, II "-A3 or II" -A4, ring B is selected from:

in other embodiments of the process of the present invention, in the compounds of formula II-A1, II-A2, II-A3, II ' -A1, II ' -A2, II ' -A3, II "-A1, II" -A2, II "-A3 or II" -A4, ring B is selected from:

in some embodiments of the methods of the present invention, in the compounds of formula II-A1, II-A2, II-A3, II ' -A1, II ' -A2, II ' -A3, II "-A1, II" -A2, II "-A3, or II" -A4, x is 1 to 3. In other embodiments, x is 1 to 3, and each R³Independently selected from hydrogen, halogen, CN, CF₃、NO₂Or optionally substituted groups selected from: c_1-6Aliphatic radical, C_1-6Alicyclic group, C_6-10Aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, arylalkyl, -N (R')₂、-CH₂N(R′)₂、-OR′、-CH₂OR′、-SR′、-CH₂SR′、-C(O)R′、-COOR′、-NRCOR′、-CON(R′)₂、-S(O)₂R', or-S (O)₂N(R′)₂. In other embodiments, x is 1-2, and each R³Is methyl, ethyl, propyl, isopropyl, tert-butyl, sec-butyl or an optionally substituted group selected from: c_1-6Aliphatic radical, C_6-10Aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl or aralkyl.

In some embodiments of the methods of the present invention, in the compound of formula II-A1, II-A2, II-A3, II ' -A1, II ' -A2, II ' -A3, II "-A1, II" -A2, II "-A3, or II" -A4, each R⁴And, when present, is hydrogen. In other embodiments, each R is⁴When present, is independently selected from hydrogen, halogen, CN, NO₂Or optionally substituted groups selected from: c_1-6Aliphatic, aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, aralkyl, -N (R')₂、-CH₂N(R′)₂、-OR′、-CH₂OR′、-SR′、-CH₂SR′、-C(O)R′、-COOR′、-NR′COR′、-CON(R′)₂or-S (O)₂N(R′)₂。

In some embodiments of the methods of the present invention, in the compound of formula II-A1, II-A2, or II-A3, R^ASelected from SO₂N(R²)₂Or SO₂R¹。

In some embodiments of the methods of the present invention, in the compound of formula II-A1, II-A2, or II-A3, R^AIs SO₂N(R²)₂And two R are²Are all hydrogen.

In some embodiments of the methods of the present invention, in the compound of formula II-A1, II-A2, or II-A3, R^AIs SO₂R¹And R is¹Is C_1-6An alkyl group.

In some embodiments of the methods of the inventionIn the compounds of the formulae II ' -A1, II ' -A2 or II ' -A3, R^AIs SO₂N(R²)₂And two R are²Are all hydrogen.

In some embodiments of the methods of the present invention, in the compound of formula II' -A4, in SO₂N(R²)₂In two, R²Are all hydrogen.

Table 1: a compound of formula I:

compositions, formulations and applications of the compounds of the invention

In another embodiment, the present invention provides a pharmaceutical composition comprising any compound of any formula or class described herein. In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of table 1.

In another embodiment, the composition further comprises an additional therapeutic agent.

According to another embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle. In one embodiment, the amount of compound in the composition of the invention is such that the voltage-gated sodium ion channel is effectively, moderately inhibited. The compounds of the invention may therefore be used to treat diseases, disorders and conditions in biological samples or patients, including but not limited to acute, chronic, neuropathic or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, neuralgia in general, epilepsy or epileptic disorders, neurodegenerative diseases, psychiatric disorders such as anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome and incontinence. Preferably, the compositions of the present invention are formulated for administration to a patient in need of such a composition. Most preferably, the compositions of the present invention are formulated for oral administration to a patient.

The term "patient" as used herein refers to an animal, preferably to a mammal, most preferably to a human.

It will also be appreciated that certain compounds of the invention can be present in free form or, where appropriate, in the form of a pharmaceutically acceptable derivative thereof for use in therapy. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adduct or derivative that upon administration to a patient in need thereof is capable of providing, directly or indirectly, a compound as described herein or a metabolite or residue thereof.

The term "pharmaceutically acceptable salt" as used herein refers to the following salts: which is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, and at a reasonable benefit/risk ratio. "pharmaceutically acceptable salt" refers to any non-toxic salt or ester salt of a compound of the present invention which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present invention or an inhibitory metabolite or residue thereof.

Pharmaceutically acceptable salts are well known in the art. For example, s.m.berge et al, in j.pharmaceutical Sciences, 66: 1-Pharmaceutically acceptable salts are described in detail in 1977, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are amino salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, embonate, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, salts, Pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like. Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium and N⁺(C_1-4Alkyl radical)₄A salt. The present invention also includes the quaternization products of any basic nitrogen-containing group of the compounds as disclosed herein. Water or oil-soluble or dispersible products can be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include those utilizing counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C, as appropriate_1-8Non-toxic ammonium, quaternary ammonium and amine cation salts of sulfonates and arylsulfonates,

as noted above, the pharmaceutically acceptable compositions of the present invention also comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, as used herein, including any and all solvents, diluents, or other liquid excipients, dispersing or suspending agents, surfactants, isotonicity agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as appropriate for the particular dosage form desired. In Remington: the Science and Practice of pharmacy, 21st edition, 2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of pharmaceutical technology, eds.J.Swarbrick and J.C.Boylan, 1988. Bucker, Marcel Dekker, New York, disclose various carriers for formulating pharmaceutically acceptable compositions and known techniques for their preparation, The contents of which are incorporated herein by reference. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention (e.g., exhibits any undesirable biological effect or otherwise interacts in a deleterious manner with any other component of a pharmaceutically acceptable composition), its use is contemplated as falling within the scope of the present invention.

Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates), glycine, sorbic acid or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block copolymers, lanolin, sugars (e.g., lactose, glucose and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered gum tragacanth; malt; gelatin; talc powder; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols such as propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; ringer's solution; ethanol; and phosphate buffers, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate; coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preserving and anti-oxidizing agents may also be present in the composition, according to the judgment of the person skilled in the art.

The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, intravaginally, or via an implant reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intraocular, intrahepatic, internal wound and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of the invention may be aqueous or oleaginous suspensions. These suspensions may be formulated according to the techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Acceptable carriers and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants such as tweens, spans and other emulsifying agents or bioavailability enhancers which are commonly used in the preparation of pharmaceutically acceptable solid, liquid or dosage forms may also be used for formulation purposes.

The pharmaceutically acceptable compositions of the present invention may be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an oral aqueous suspension is desired, the active ingredient is mixed with emulsifying and suspending agents. Certain sweetening, flavoring or coloring agents may also be added, if desired.

Alternatively, the pharmaceutically acceptable compositions of the present invention may be in the form of suppositories for rectal administration. These suppositories can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at room temperature but liquid at intestinal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutically acceptable compositions of the present invention may also be administered topically, particularly when the target of treatment includes diseases of areas or organs readily accessible by topical administration, including the eye, skin or lower intestinal tract. Suitable topical formulations for use in various areas or organs are readily prepared.

Topical administration to the lower intestinal tract may be accomplished by rectal suppository (see above) or in a suitable enema. Topical transdermal patches may also be used.

For topical use, the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid paraffin, white soft paraffin, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutically acceptable composition may be formulated as a suitable lotion or emulsion comprising the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutically acceptable compositions may be formulated as micronized suspensions, for example, in isotonic, pH adjusted sterile saline or other aqueous solutions, or preferably as solutions in isotonic, pH adjusted sterile saline or other aqueous solutions, with or without preservatives such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable composition may be formulated into an ointment such as petrolatum. The pharmaceutically acceptable compositions of the present invention may also be administered by nasal spray or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and/or other conventional solubilizing or dispersing agents.

Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, for example ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butanediol, dimethylformamide, oils (in particular cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations (e.g., sterile injectable aqueous or oleaginous suspensions) may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable carriers and solvents that may be employed are water, ringer's solution, U.S. p. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids, such as oleic acid, may be used in the preparation of injectables.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of the compounds of the invention, it is often desirable to delay absorption of the compounds following subcutaneous or intramuscular injection. This can be achieved using liquid suspensions of crystalline or amorphous materials that are poorly water soluble. The rate of absorption of a compound depends on its rate of dissolution, which in turn depends on crystal size and crystalline form. Alternatively, the compound is dissolved or suspended in an oil medium to achieve delayed absorption of the parenterally administered compound form. Injectable depot formulations can be prepared by forming microencapsule matrices of the compounds in biodegradable polymers such as polylactide-glycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot (depot) injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissues.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or suppository waxes which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and/or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) wetting agents, such as glycerol, d) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) dissolution retarders, such as paraffin, f) adsorption accelerators, such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and glycerol monostearate, h) adsorbents, such as kaolin and bentonite, and i) lubricants, such as talc, Calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. For capsules, tablets and pills, these dosage forms may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft or hard filled capsules using excipients such as lactose or milk sugar as well as polymeric polyethylene glycols and the like. Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft or hard filled capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The active compound may also be in microencapsulated form and contain one or more excipients as described above. Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In these solid dosage forms, the active compound may be mixed with at least one inert diluent, for example sucrose, lactose or starch. Normally, these dosage forms may also contain other substances in addition to inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. For capsules, tablets and pills, these dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and may also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of the compounds of the invention include ointments, pastes, emulsions (creams), lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any required preservatives or buffers, as appropriate. Ophthalmic formulations, ear drops and eye drops are also encompassed within the scope of the present invention. In addition, the present invention encompasses the use of transdermal patches, which have the added advantage of controlling the delivery of compounds to the body. Such dosage forms may be prepared by dissolving or dispersing the compound in the appropriate medium. Absorption enhancers may also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

The compounds of the present invention are preferably formulated in unit dosage form to facilitate administration and maintain dose uniformity. The phrase "unit dosage form" as used herein refers to a physically discrete unit of medicament suitable for the patient to be treated. However, it will be understood that the total daily amount of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend upon a variety of factors including the disease to be treated and the severity of the disease; the activity of the particular compound used; the specific composition used; the age, weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the particular compound used; the duration of the treatment; drugs used in combination or concomitantly with the specific compound employed, and similar factors well known in the medical arts.

The amount of a compound of the present invention that may be combined with a carrier material to produce a composition in a single dosage form will vary depending upon the host treated and the particular mode of administration. The pharmaceutically acceptable compositions of the present invention may be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as powders, ointments, or drops), buccally, as an oral or nasal spray, and the like, depending on the severity of the infection to be treated. In certain embodiments, the compounds of the present invention may be administered orally or parenterally at a dosage level of from about 0.01mg/kg to about 50mg/kg, preferably from about 1mg/kg to about 25mg/kg, of the subject's body weight per day, one or more times per day, to achieve the desired therapeutic effect.

Depending on the particular condition or disease to be treated or prevented, other therapeutic agents that are commonly employed in treating or preventing such conditions may also be present in the compositions of the present invention. As used herein, other therapeutic agents that are typically administered to treat or prevent a particular disease or condition are considered "appropriate for the disease or condition being treated.

The amount of the other therapeutic agent in the composition of the present invention does not exceed the amount that would normally be present in a composition containing the therapeutic agent as the only active agent. Preferably, the other therapeutic agent is present in the compositions disclosed herein at a level of from about 50% to 100% of its level typically present in compositions containing the therapeutic agent as the sole therapeutically active agent.

Use of the Compounds and compositions of the invention

According to one embodiment, the present invention relates to a method of inhibiting sodium channel activity in a biological sample comprising contacting the biological sample with a compound of the present invention or a composition comprising the compound. The term "biological sample" as used herein refers to a sample that is external to a living organism, including but not limited to cell cultures or extracts thereof; biopsy material obtained from a mammal or an extract thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. The effect of inhibiting sodium channel activity in a biological sample can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, biological sample storage and biological assays. In one embodiment, the method of inhibiting sodium channel activity in a biological sample is limited to non-therapeutic methods.

In some embodiments, the present invention relates to a method of treating or lessening the severity of: acute, chronic, neuropathic or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy or epileptic disorders, neurodegenerative diseases, psychiatric disorders such as anxiety and depression, bipolar disorders, myotonia, cardiac arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritic pain, post-herpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, penetrating pain, post-operative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-or exercise-induced angina, palpitation, hypertension, migraine or abnormal gastrointestinal activity, comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable group comprising the compound The compound is administered to a patient in need thereof.

The term "subject" as used herein refers to an animal, preferably a mammal, most preferably a human.

In some embodiments, the invention relates to a method of treating or reducing the severity of acute, chronic, neuropathic, or inflammatory pain.

In another embodiment, the invention relates to a method of treating or lessening the severity of: radicular pain, sciatica, back pain, headache, neck pain, intractable pain, acute pain, post-operative pain, back pain, tinnitus, or cancer pain.

In another embodiment, the invention relates to a method of treating or lessening the severity of: femoral cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic lumbago; neuropathic lumbago; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, including abdominal pain; pain in the pancreas; IBS pain; chronic and acute headache; migraine headache; tension headaches, including cluster headaches; chronic and acute neuropathic pain, including post-herpetic neuralgia; diabetic neuropathy; HIV-related neuropathies; trigeminal neuralgia; charcot-horse-charcot-type neuropathy; hereditary sensory neuropathy; peripheral nerve damage; painful neuroma; ectopic proximal and distal discharges; a radiculopathy; chemotherapy-induced neuropathic pain; radiotherapy-induced neuropathic pain; pain after mastectomy; central pain; pain from spinal cord injury; pain following stroke; thalalgia; complex regional pain syndrome; phantom pain; intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; injury/athletic pain; acute visceral pain, including abdominal pain; pyelonephritis; appendicitis; cholecystitis (cholecystitis); ileus; hernia, etc.; chest pain, including cardiac pain; pelvic pain, renal colic, acute obstetric pain, including childbirth pain; cesarean pain; acute inflammatory pain, burn pain, and wound pain; acute intermittent pain, including endometriosis; acute herpes zoster pain; sickle cell disease; acute pancreatitis; breakthrough pain; or oral and facial pain, including sinusitis pain, dental pain; multiple Sclerosis (MS) pain; pain in depression; leprosy pain; behcet's disease pain; painful obesity; phlegmonotic pain; Guillain-Barre disease (Guillain-Barre) pain; lower limb pain and toe movement; haglund syndrome; erythematous limb pain; fabry's disease pain; bladder and genitourinary disorders, including urinary incontinence; overactive bladder; painful bladder syndrome; interstitial Cystitis (IC); or prostatitis; complex regional pain syndrome of type I and type II (CRPS); or angina-induced pain.

As generally described above, the compounds of the present invention are useful as inhibitors of voltage-gated sodium ion channels. In one embodiment, the compounds and compositions of the present invention are inhibitors of one or more of nav1.1, nav1.2, nav1.3, nav1.4, nav1.5, nav1.6, nav1.7, nav1.8 or nav1.9 and thus, without wishing to be bound by any particular theory, are particularly useful for treating or lessening the severity of a disease, condition or disorder associated with an overactivity or activity of one or more of nav1.1, nav1.2, nav1.3, nav1.4, nav1.5, nav1.6, nav1.7, nav1.8 or nav 1.9. When activation or overactivity of nav1.1, nav1.2, nav1.3, nav1.4, nav1.5, nav1.6, nav1.7, nav1.8 or nav1.9 is associated with a particular disease, condition or disorder, the disease, condition or disorder may also be referred to as a "nav 1.1, nav1.2, nav1.3, nav1.4, nav1.5, nav1.6, nav1.7, nav1.8 or nav 1.9-mediated disease, condition or disorder". Thus, in another aspect, the invention provides a method of treating or lessening the severity of a disease, condition or disorder, wherein activation or hyperactivity of one or more of nav1.1, nav1.2, nav1.3, nav1.4, nav1.5, nav1.6, nav1.7, nav1.8 or nav1.9 is associated with the disease state.

The activity of compounds used in the present invention as inhibitors of nav1.1, nav1.2, nav1.3, nav1.4, nav1.5, nav1.6, nav1.7, nav1.8 or nav1.9 can be determined according to the methods generally described in the examples herein or according to methods available to one of ordinary skill in the art.

It is to be understood that the compounds and pharmaceutically acceptable compositions of the present invention can be used in combination therapy, that is, the compounds and pharmaceutically acceptable compositions can be administered simultaneously with, before, or after one or more other desired therapeutic agents or procedures. The particular combination of therapies (therapeutic agents or therapeutic procedures) used in a combination regimen requires consideration of the compatibility of the desired therapeutic agent and/or procedure with the desired therapeutic effect to be achieved. It will also be appreciated that the therapies used may achieve the desired effect on the same condition (e.g., the compounds of the invention may be administered simultaneously with another drug used to treat the same condition), or they may achieve different effects (e.g., control of any adverse effects). Other therapeutic agents commonly administered for the treatment or prevention of a particular disease or condition, as used herein, are considered "appropriate for the disease or condition being treated". For example, exemplary other therapeutic agents include, but are not limited to: non-opioid analgesics (indoles such as etodolac, indomethacin, sulindac, tolmetin, naphthylalkanones such as nabumetone, oxicams such as piroxicam, acetaminophen derivatives such as acetaminophen, propionic acids such as fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen sodium, oxaprozin, salicylic acids such as aspirin, choline magnesium trisalicylate, diflunisal, fenamates such as meclofenamic acid, mefenamic acid, and pyrazoles such as phenylbutazone); or an opioid (narcotic) agonist (e.g., codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, dextropropoxyphene, buprenorphine, butorphanol, dezocine, nalbuphine, and pentazocine). In addition, non-pharmaceutical analgesic methods may be used in conjunction with the administration of one or more compounds of the present invention. For example, it is also possibleAnaesthesia methods (intraspinal infusion, nerve blocking), neurosurgery (neurolysis of CNS pathways), neurostimulation (transcutaneous electrical nerve stimulation, dorsal column stimulation), physical therapy (physiotherapy, orthopedic instruments, diathermy), or psychology (cognitive methods-hypnosis, biofeedback or behavioral therapy) are used. Other suitable therapeutic agents or methods of treatment are generally described in the merck Manual, 17 th edition, edited by Mark h. beers and Robert Berkow, merck research Laboratories, 1999; the Merck Manual, 18 th edition, edited by Mark H.Beers and Robert S.Porter, Merck Research Laboratories, 2006, and The U.S. food and drug administration Web site,www.fda.govis incorporated herein by reference in its entirety.

Those additional agents may be administered separately from the compositions comprising the compounds of the present invention as part of a multiple (dose) regimen. Alternatively, those drugs may be part of a single dosage form, mixed in a separate composition with the compound of the invention. If administered as part of a multiple dosing regimen, the two active agents can be administered simultaneously, sequentially or at intervals from each other (typically within 5 hours of each other).

The amount of both the compound of the invention and the other therapeutic agent (in those compositions containing the other therapeutic agent as described above) that can be mixed with the carrier material to produce a single dosage form will vary depending on the host treated and the particular mode of administration. Preferably, the compositions of the present invention should be formulated such that about 0.01-100mg/kg body weight/day of the compound of formula I can be administered.

In those compositions that include other therapeutic agents, the other therapeutic agents and the compounds of the invention may act synergistically. Thus, the amount of the other therapeutic agent in these compositions is less than that required in a monotherapy employing only that therapeutic agent. In these compositions, other therapeutic agents may be administered at doses ranging from 0.01 to 100mg/kg body weight/day.

The amount of the other therapeutic agent in the composition of the present invention should not exceed the amount that would normally be present in a composition containing the therapeutic agent as the only active agent. Preferably, the amount of the additional therapeutic agent in the presently disclosed compositions is from about 50% to 100% of its content typically present in compositions containing the therapeutic agent as the sole therapeutically active agent.

The compounds of the present invention or pharmaceutically acceptable compositions thereof may also be incorporated into compositions for coating implantable medical devices, such as prostheses, prosthetic valves, vascular prostheses, stents, and catheters. Thus, in another aspect, the present invention includes a composition for coating an implantable device, the composition comprising a compound of the present invention as generally described above and in classes and subclasses herein, and a carrier suitable for coating the implantable device. In another aspect, the invention includes an implantable device coated with a composition comprising a compound of the invention as generally described above and in classes and subclasses herein, and a carrier suitable for coating the implantable device. General methods for making suitable coatings and coated implantable devices are described in U.S. Pat. Nos. 6,099,562, 5,886,026, and 5,304,121. The coating is typically a biocompatible polymeric material such as hydrogel polymers, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate copolymers, and mixtures thereof. The coating may optionally be further covered by a surface layer of a suitable fluorosilicone, polysaccharide, polyethylene glycol, phospholipid, or combinations thereof, to impart controlled release characteristics to the composition. Implantable devices coated with the compounds of the present invention are another embodiment of the present invention.

Another aspect of the invention relates to inhibiting nav1.1, nav1.2, nav1.3, nav1.4, nav1.5, nav1.6, nav1.7, nav1.8 or nav1.9 activity in a biological sample or patient, comprising administering to the patient, or contacting said biological sample with a compound of formula I or a composition comprising the compound. The term "biological sample" as used herein includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from a mammal or an extract thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of nav1.1, nav1.2, nav1.3, nav1.4, nav1.5, nav1.6, nav1.7, nav1.8 or nav1.9 activity in a biological sample may be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, storage of biological samples, biological assays, studies of sodium ion channels in biological and pathological phenomena; and comparative evaluation of novel sodium channel inhibitors. In one embodiment, the method of inhibiting sodium channel activity in a biological sample is limited to non-therapeutic methods.

In order that the invention described herein may be more fully understood, the following examples are provided. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the invention in any way.

Preparation of the Compounds of the invention

The following definitions describe terms and abbreviations used herein:

ac acetyl group

Bu butyl

Et Ethyl group

Ph phenyl

Me methyl group

Boc tert-butyloxycarbonyl group

THF tetrahydrofuran

DCM dichloromethane

CH₂Cl₂Methylene dichloride

EtOAc ethyl acetate

CH₃CN acetonitrile

EtOH ethanol

MeOH methanol

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

HOAc acetic acid

TFA trifluoroacetic acid

BOP benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate

EDC 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

4-DMAP 4-dimethylaminopyridine

HATU N- [ (dimethylamino) -1-H-1, 2, 3-triazolo [4, 5, 6] -pyridine

Pyridin-1-ylmethylene ] -N-methylmethanaminium hexafluorophosphate N-oxide

Article of manufacture

SOCl₂Thionyl chloride

POCl₃Phosphorus oxychloride

Et₃N-Triethylamine

DIPEA diisopropylethylamine

DIEA diisopropylethylamine

K₂CO₃Potassium carbonate

Na₂CO₃Sodium carbonate

Cs₂CO₃Cesium carbonate

NaHCO₃Sodium bicarbonate

NaOH sodium hydroxide

KOH potassium hydroxide

LiOH lithium hydroxide

Na₂SO₄Sodium sulfate

CuSO₄Copper sulfate

(CuOTf)₂PhH copper (I) trifluoromethanesulfonate benzene complex

Et₃OBF₄Triethyloxonium tetrafluoroborate

MS 4 angstrom molecular sieve

LC/MS liquid chromatography/Mass Spectrometry

HPLC high performance liquid chromatography

hr hour

atm atmospheric pressure

RT or RT Room temperature

Other abbreviations, symbols, and idioms are used herein as used in the contemporary scientific literature. See, e.g., Janet s.dodd editors, The ACS Style Guide: a Manual for Authors and Editors, 2nd ed., Washington, d.c.: american Chemical Society, 1997, which is incorporated herein by reference in its entirety.

General synthetic methods

In general, the compounds of the invention may be prepared by the methods described herein or known to those skilled in the art for preparing analogous compounds. In order that the invention described herein may be more fully understood, the following examples are provided. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the invention in any way.

The following synthetic schemes a and B illustrate exemplary methods of preparing compounds of formula I. Scheme A is used to prepare compounds 1-4, 7-22, 24 and 28-34 of Table 1 of the present invention. Scheme B is used to prepare compound 23 of the present invention in table 1. Scheme C is used to prepare compound 25 of the present invention, table 1. Scheme D is useful for the preparation of compounds 26-27 of Table 1 of the present invention. Scheme E is used to prepare compounds 5-6 of table 1 of the present invention.

Synthesis scheme A：

Conditions are as follows: (a) SOCl₂，CH₂Cl₂(ii) a Pyridine; (b) HATU, Et₃N，DMF(c)BOP，Et₃N，CH₂Cl₂

Synthesis scheme B：

Conditions are as follows: (a) LiOH, THF, H₂O；(b)HATU，Et₃N，DMF

Synthesis scheme C：

Conditions are as follows: (a) r³-OCl，Et₃N，CH₂Cl₂；(b)POCl₃；(c)LiOH，THF，H₂O；(d)HATU，Et₃N，DMF

Synthesis route D：

Conditions are as follows: (a) et (Et)₃OBF₄，CH₂Cl₂；(b)Et₃N，CH₂Cl₂；(c)LiOH，THF，H₂O；(d)HATU，DMF

Synthesis scheme E：

Conditions are as follows: (a) HN (R')₂Acetone; (b) LiOH, THF, H₂O；(c)HATU，Et₃N，DMF

Examples of suitable peptide coupling agents include DCC (dicyclohexylcarbodiimide), DIC (diisopropylcarbodiimide), di-p-toluoylcarbodiimide, BDP (1-benzotriazolediethylphosphate-1-cyclohexyl-3- (2-morpholinoethyl) carbodiimide), EDC (1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride), cyanuric fluoride, cyanuric chloride, TFFH (tetramethylfluorourea hexafluorophosphate), DPPA (diphenylphosphoryl azide), BOP (benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate), HBTU (O-benzotriazol-1-yl-N, N, N ', N' -tetramethyluronium hexafluorophosphate), TBTU (O-benzotriazol-1-yl-N, n, N ', N' -tetramethyluronium tetrafluoroborate), TSTU (O- (N-succinimide) -N, N, N ', N' -tetramethyluronium tetrafluoroborate), HATU (N- [ (dimethylamino) -1-H-1, 2, 3-triazolo [4, 5, 6] -pyridin-1-ylmethylene ] -N-methylmethanamine hexafluorophosphate N-oxide), BOP-Cl (bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride), PyBOP ((1-H-1, 2, 3-benzotriazol-1-yloxy) -tris (pyrrolidinyl) phosphonium tetrafluorophosphate), BrOP (bromotris (dimethylamino) phosphonium hexafluorophosphate), DEPBT (3- (diethoxyphosphoryloxy) -1, 2, 3-benzotriazin-4 (3H) -one), or PyBrOP (bromotris (pyrrolidinyl) phosphonium hexafluorophosphate). Alternative reagents that may be used in the amide bond formation reaction include DMAP (4-dimethylaminopyridine) or active ester reagents such as HOBT (1-hydroxybenzotriazole), HOAT (1-hydroxy-7-azobenzotriazole), HOSu (N-hydroxysuccinimide), and HONB (endo-N-hydroxy-5-norbornene-2, 3-dicarboximide).

Synthetic examples

General procedure

From deuterated chloroform (CDCl)₃) Or dimethyl sulfoxide-D₆(DMSO) solution was obtained¹HNMR (400MHz) and¹³c NMR (100MHz) spectrum. Using PESciex API-150-EXLC/MS, Shimadzu LC-8A pump, Gilson 215 autosampler, Gilson 819 injection Module, flow rate of 3.0 mL/min, 10-99% CH₃CN(0.035％TFA)/H₂LC/MS data were obtained with an O (0.05% TFA) gradient, a Phenomenex Luna 5. mu. m C18 column (50X4.60mm), a Shimadzu SPD-10A UV/Vis detector, a Cedex 75 ELSD detector. Silica gel chromatography was performed using silica gel-60 with a particle size of 230-400 mesh. Pyridine, methylene Chloride (CH)₂Cl₂) And Tetrahydrofuran (THF) from an Aldrich Sure-Seal bottle kept under dry nitrogen. All reactions were magnetically stirred unless otherwise indicated. All temperatures refer to internal reaction temperatures unless otherwise indicated.

In order to more fully understand the present invention, the following preparation examples are set forth. These examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

6-tert-butyl-N- (3- (aminosulfonyl) phenyl) pyridine-3-carboxamide

A solution of 6-tert-butylpyridine-3-carboxylic acid (18mg, 0.10mmol) and HATU (38mg, 0.10mmol) in DMF (1mL) was stirred at room temperature for 3 min. To this solution was added 3-amino-benzenesulfonamide (17mg, 0.10mmol) and triethylamine (28. mu.L, 0.20 mmol). The reaction solution was stirred at room temperature for 16 hours and purified by preparative reverse phase HPLC using 10% -99% CH₃CN(0.035％TFA)/H₂Elution with O (0.05% TFA) gave 6-tert-butyl-N- (3- (aminosulfonyl) phenyl) pyridine-3-carboxamide.

LC/MS：m/z 334.3(M+H)⁺At 1.99 min (10% -99% CH)₃CN(0.035％TFA)/H₂O(0.05％TFA))。

5-tert-butyl-1, 3, 4-thiadiazole-2-carboxylic acid lithium salt

A solution of ethyl 5-tert-butyl-1, 3, 4-thiadiazole-2-carboxylate (0.21g, 1.0mmol) and lithium hydroxide hydrate (42mg, 1.0mmol) in THF (2mL) and water (2mL) was stirred at room temperature for 18 hours. The solvent was removed in vacuo to give lithium 5-tert-butyl-1, 3, 4-thiadiazole-2-carboxylate (0.2g) as a white solid, which was used without further purification.

5-tert-butyl-N- (3-aminosulfonylphenyl) -1, 3, 4-thiadiazole-2-carboxamide (Compound 23)

A solution of lithium 5-tert-butyl-1, 3, 4-thiadiazole-2-carboxylate (0.2g, 1mmol) and HATU (0.38g, 1.0mmol) in DMF (5mL) was stirred at room temperature for 10 min, then 3-amino-benzenesulfonamide (0.17g, 1.0mmol) was added. The reaction was stirred for 4 hours, diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine and water, dried over sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel eluting with 0-5% methanol in dichloromethane to give 5-tert-butyl-N- (3-aminosulfonylphenyl) -1, 3, 4-thiadiazole-2-carboxamide (107mg, 31% yield).

LC/MS：m/z 341.1(M+H)⁺At 2.79 min (10% -99% CH)₃CN(0.035％TFA)/H₂O(0.05％TFA))。

3-oxo-2- (pivaloylamino) butanoic acid methyl ester

Methyl 2-amino-3-oxobutanoate hydrochloride (0.50g, 3.0mmol) in CH₂Cl₂The solution (30mL) was cooled in an ice bath. Pivaloyl chloride (0.37mL, 3.0mmol) and triethylamine (0.84mL, 6.0mmol) were added slowly and the reaction was allowed to warm slowly to room temperature overnight. The reaction system was washed with water and Na₂SO₄Dried and concentrated in vacuo. The residue was purified by silica gel chromatography (0% to 3% MeOH-CH)₂Cl₂) To give methyl 3-oxo-2- (pivaloylamino) butanoate (0.48g, 74% yield).

¹H NMR(400MHz，CDCl₃)δ6.82(bs，1H)，5.21(d，J＝6.1Hz，1H)，3.82(s，3H)，2.39(s，3H)，1.24(s，9H)ppm。

LC/MS：m/z 216.5(M+H)⁺At 1.98 min (10% -99% CH)₃CN(0.035％TFA)/H₂O(0.05％TFA))。

2-tert-butyl-5-methyloxazole-4-carboxylic acid methyl ester

A solution of methyl 3-oxo-2- (pivaloylamido) butyrate (0.22g, 1.0mmol) in phosphorus oxychloride (1.5mL) was heated at 110 ℃ for 30 minutes. The reaction was cooled in an ice bath and saturated NaHCO was slowly added₃Aqueous solution until the mixture is alkaline. Using CH for the reaction solution₂Cl₂Extracting, and subjecting the extractive solution to NaHCO₃Saturated aqueous solution and water, washed with Na₂SO₄Dried and concentrated in vacuo. The residue was purified by silica gel chromatography (0% -40% EtOAc-hexanes) to give methyl 2-tert-butyl-5-methyloxazole-4-carboxylate (44mg, 22% yield).

¹H NMR(400MHz，CDCl₃)δ3.90(s，3H)，2.60(s，3H)，1.39(s，9H)ppm。

LC/MS：m/z 198.3(M+H)⁺At 2.83 minutes (10% -99% CH)₃CN(0.035％TFA)/H₂O(0.05％TFA))。

2-tert-butyl-5-methyloxazole-4-carboxylic acid

A mixture of methyl 2-tert-butyl-5-methyloxazole-4-carboxylate (44mg, 0.22mmol) and lithium hydroxide hydrate (47mg, 1.1mmol) in THF (1mL) and water (1mL) was stirred at room temperature for 19 hours. Adding 1M HCl into the reaction system_(aq)(1.1mL, 1.1mmol) and water, and the reaction was extracted with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate and evaporated to give 2-tert-butyl-5-methyloxazole-4-carboxylic acid (40 m)g, 98% yield) as a white solid.

¹H NMR(400MHz，CDCl₃)δ2.61(s，3H)，1.38(s，9H)ppm。

5-tert-butyl-2-benzyl-2H-1, 2, 4-triazole-3-carboxylic acid ethyl ester

Ethyl thiooxamate (0.27g, 2.0mmol) and triethyloxonium tetrafluoroborate (0.40g, 2.1mmol) in CH₂Cl₂(25mL) the solution was stirred at room temperature for 2 h. The reaction was cooled in an ice bath and N' -benzylpivaloyl hydrazide (0.41g, 2.0mmol) and triethylamine (0.28mL, 2.0mmol) in CH was added slowly₂Cl₂(10mL) of the solution. The cooling bath was removed and the reaction was heated to reflux for 90 minutes. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (0% -25% EtOAc-hexanes) to give ethyl 5-tert-butyl-2-benzyl-2H-1, 2, 4-triazole-3-carboxylate (0.23g, 40% yield).

¹H NMR(400MHz，CDCl₃)δ7.34-7.28(m，5H)，5.73(s，2H)，4.43(q，J＝7.1Hz，2H)，1.40(s，9H)，1.38(t，J＝7.7Hz，3H)ppm。

LC/MS：m/z 288.2(M+H)⁺At 3.51 min (10% -99% CH)₃CN(0.035％TFA)/H₂O(0.05％TFA))。

5-tert-butyl-2-benzyl-N- (3- (aminosulfonyl) phenyl) -2H-1, 2, 4-triazole-3-carboxamide (Compound 26)

Reacting 5-tert-butyl-2-benzyl-2H-1, 2, 4-triazole-3-carboxylic acid ethyl ester(0.10g, 0.35mmol) and LiOH. H₂O (29mg, 0.70mmo l) in THF (1mL) and H₂The suspension in O (1mL) was stirred at room temperature for 2 hours. The solvent was evaporated in vacuo and DMF (2mL) and HATU (0.13g, 0.35mmol) were added to the residue. The reaction was stirred for 3 min, then 3-amino-benzenesulfonamide (60mg, 0.35mmol) was added. The reaction was stirred for 3 hours, diluted with water and extracted with EtOAc. The organic extract was washed with water and Na₂SO₄Dried and concentrated in vacuo. The residue was purified by silica gel chromatography (0% to 5% MeOH-CH)₂Cl₂) To give 5-tert-butyl-2-benzyl-N- (3- (aminosulfonyl) phenyl) -2H-1, 2, 4-triazole-3-carboxamide (16mg, 11% yield).

LC/MS：m/z 414.3(M+H)⁺At 3.46 min (10% -99% CH)₃CN(0.035％TFA)/H₂O(0.05％TFA))。

5-tert-butyl-2- (bromomethyl) furan-3-carboxylic acid methyl ester

A mixture of methyl 5-tert-butyl-2-methylfuran-3-carboxylate (10.4g, 53mmol), N-bromosuccinimide (9.9g, 55mmol), and azobisisobutyronitrile (0.1g, 0.6mmol) in carbon tetrachloride (100mL) was heated at reflux for 1.5 hours. The suspension was cooled to room temperature, the succinimide was removed by filtration and rinsed with carbon tetrachloride. The combined filtrates were evaporated to dryness. The residue was subjected to Kuge lrohr distillation (< 1mbar, 110-.

¹H-NMR(300MHz，CDCl₃)：δ6.28(s，1H)，4.80(s，2H)，3.85(s，3H)，1.28(s，9H)ppm。

5-tert-butyl-2- ((piperidin-1-yl) methyl) furan-3-carboxylic acid methyl ester

A solution of methyl 5-tert-butyl-2- (bromomethyl) furan-3-carboxylate (0.28g, 1.0mmol) and piperidine (99. mu.L, 1mmol) in acetone (5mL) was stirred at room temperature for 3 days. The mixture was diluted with water and extracted with EtOAc. The organic extracts were washed with water and Na₂SO₄Dried and concentrated in vacuo. The residue was purified by silica gel chromatography (0% -50% EtOAc-hexanes) to give methyl 5-tert-butyl-2- ((piperidin-1-yl) methyl) furan-3-carboxylate (41mg, 15% yield).

LC/MS：m/z 280.3(M+H)⁺At 2.10 min (10% -99% CH)₃CN(0.035％TFA)/H₂O(0.05％TFA))。

The characterization data for the compounds of table 1 are shown in table 2.

TABLE 2：

Bioassay of Compounds of the invention

Assay for detecting and measuring NaV inhibitory properties of compounds

A) Optical method for determining the NaV inhibiting properties of a compound:

the compounds of the invention are useful as antagonists of voltage-gated sodium ion channels. The antagonistic properties of the test compounds were evaluated as follows. Cells expressing target NaV were placed in microtiter plates. After the incubation period, the cells are stained with a fluorescent dye sensitive to transmembrane potential. Test compounds were added to the microtiter plate. Chemically or electrically stimulating cells to stimulate NaV-dependent membrane electricity from unblocked channelsThe change in position is detected and measured using a transmembrane potential-sensitive dye. Antagonists are detected as a decrease in membrane potential in response to a stimulus. Optical membrane potentiometry employs Voltage-sensitive FRET sensors, which are manufactured by Gonzalez and Tsien (see, Gonzalez, J.E., and R.Y.Tsien (1995) 'Voltage sensing by fluorescence sensitivity transduction in single cells'Biophys J69(4): 1272-80, and Gonzalez, J.E. and R.Y.Tsien (1997) "improved dindicators of cell membrane potential that use fluorescence response energy transfer"Chem Biol4(4): 269-77) in combination with an instrument for measuring changes in fluorescence, e.g. voltage/ion probe reader (VIPR))(Referring to the description of the preferred embodiment,gonzalez, J.E., K.Oads et al, (1999) "Cell-based assays and instrumentation for screening-channel targets"Drug Discov Today 4(9)：431-439)。

Cell processing and dye Loading

1) 24 hours prior to VIPR assay, CHO cells endogenously expressing NaV1.2 type voltage-gated NaV were seeded in 96-well polylysine-coated culture plates at 60,000 cells per well.

2) On the day of assay, the medium was aspirated and the cells were washed twice with 225 μ L of bath solution No. 2 (BS # 2).

3) A15. mu.M solution of CC2-DMPE was prepared as follows: 5mM coumarin stock was mixed 1: 1 with 10% Pluronic 127 and the mixture was dissolved in an appropriate volume of BS # 2.

4) After removing the bath from the 96-well plate, the cells were loaded with 80 μ L of CC2-DMPE solution. The plates were incubated in the dark for 30 minutes at room temperature.

5) While the cells were stained with coumarin, 15 μ L of Oxonol in BS #2 was prepared. Except that DiSBAC₂(3) In addition, the solution should also contain 0.75mM ABSC1 and 30. mu.L veratridine (prepared from 10mM EtOH stock, Sigma # V-5754).

6) After 30 min, CC2-DMPE was removed and cells were washed twice with 225. mu.L of BS # 2. As mentioned before, the residual volume should be 40. mu.L.

7) After removing the bath, cells were loaded with 80 μ L of DiSBAC₂(3) Solutions were then added to each well from the dosing plate in DMSO solution of test compound to achieve the desired assay concentration, mixed well. The volume in the wells should be about 121 μ L. The cells were then incubated for 20-30 minutes.

8) Once incubation is complete, the sodium addition protocol can be used in VIPRThe cells were assayed as above. 120 μ L of bath No. 1 was added to stimulate NaV-dependent depolarization. 200 μ L of tetracaine was used as a positive control for complete blockade of the NaV channel.

Na⁺Add back analysis window: baseline 2-7 seconds, and final 15-24 seconds.

Solution [ mM ]]

No. 1 bath lotion: NaCl 160, KCl 4.5, CaCl₂ 2，MgCl₂HEPES 10, pH7.4 (adjusted with NaOH)

No. 2 bath lotion: TMA-Cl 160, CaCl₂ 0.1，MgCl₂1, HEPES 10, pH7.4 (with KOH) (final K concentration 5mM)

CC 2-DMPE: 5mM DMSO stock solution was prepared and stored at-20 deg.C

DiSBAC₂(3): prepared into 12mM DMSO stock solution, stored at-20 deg.C

ABSC 1: prepared into 200mM distilled water mother liquor, stored at room temperature

Cell culture

CHO cells were grown in DMEM (Dulbecco's modified Eagle Medium; GibcoBRL #10569-010) supplemented with 10% FBS (fetal bovine serum, eligible; GibcoBRL #16140-071) and 1% Pen-Strep (penicillin-streptomycin; GibcoBRL # 15140-122). Cells were grown in vented flasks with caps at 90% humidity and 10% CO₂Medium growth to 100% confluence. They are usually cleaved by trypsin digestion to 1: 10 or 1: 20, as required by the program, and grown for 2-3 days before the next cleavage.

The following is an example of how the inhibitory activity of NaV1.3 can be determined using optical film potentiometry # 2. Assays for other subtypes were performed in a similar manner in cell lines expressing the target NaV.

HEK293 cells stably expressing nav1.3 were plated into 96 well microtiter plates. After an appropriate incubation period, the cells were incubated with the voltage-sensitive dye CC2-DMPE/DiSBAC as described below₂(3) And (6) dyeing.

Reagent:

100mg/ml Pluronic F-127(Sigma # P2443) in anhydrous DMSO

10mM DiSBAC₂(3) (Aurora #00-100-010) in anhydrous DMSO

10mM CC2-DMPE (Aurora #00-100-

200mM ABSC1 at H₂In O

Hank's balanced salt solution (Hyclone # SH30268.02) supplemented with 10mM HEPES (Gibco #15630-080)

Loading scheme:

2X CC2-DMPE ═ 20 μ M CC 2-DMPE: 10mM CC2-DMPE was vortexed with an equal volume of 10% P lucon i c, followed by vortexing in the required amount of HBSS containing 10mM HEPES. 5ml of 2X CC2-DMPE was required per cell plate. To the wells containing washed cells, 50. mu.L of 2X CC2-DMPE was added, resulting in a final staining concentration of 10. mu.M. Cells were stained in the dark for 30 minutes at room temperature.

2X DISBAC₂(3) And ABSC1 ═ 6 μ M discac₂(3) And 1mM ABSC 1: add the required amount of 10mM DISBAC to 50ml conical tube₂(3) And mixed with 1 μ L of 10% Pluronic (for each ml of solution to be prepared) and vortexed. HBSS/HEPES was then added to make a 2X solution. Finally ABSC1 was added.

2X DiSBAC₂(3) The solution can be used to solvate the compound plate. Note that: compound plates were made at 2X drug concentration. The stained plate was washed again with a residual volume of 50. mu.L. Add 50. mu.L/well of 2 XSBAC₂(3) w/ABSC 1. The staining was carried out at room temperature for 30 minutes in the dark.

The electrical stimulation apparatus and methods used are described in ion channel assay PCT/US01/21652, which is incorporated herein by reference. The instrument includes a microtiter plate processor, an optical system for exciting the coumarin dye and simultaneously recording the coumarin and Oxono emissions, a waveform generator, a current or voltage controlled amplifier, and a means for inserting electrodes into the wells. Under the control of an integrated computer, the instrument performs a user-programmed electrical stimulation protocol on cells in the wells of the microtiter plate.

Reagent

No. 1 assay buffer

140mM NaCl，4.5mM KCl，2mM CaCl₂，1mM MgCl₂10mM HEPES, 10mmM glucose, pH7.40, 330mOsm

Pluronic stock (1000 ×): 100mg/ml Pluronic 127 in anhydrous DMSO

Oxonol mother liquor (3333X): 10mM DiSBAC₂(3) In anhydrous DMSO

Coumarin stock (1000X): 10mM CC2-DMPE in anhydrous DMSO

ABSC1 mother liquor (400X): 200mM ABSC1 in water

Assay protocol

1. Electrodes are inserted or used into each well to be measured.

2. The stimulus pulse was delivered for 3 seconds using a current controlled amplifier. Pre-stimulation recordings were performed for 2 seconds to obtain the intensity when unstimulated. Recording after 5 seconds of stimulation was performed to check relaxation to a resting state.

Data analysis

The data were analyzed and presented as normalized ratios of background-subtracted emission intensities measured in the 460nm and 580nm channels. The background intensity was then subtracted from each assay channel. The background intensity is obtained by: the emission intensity of the measurement wells without the presence of cells subjected to the same treatment was measured over the same time. The response as a function of time is then reported as a ratio found using the following equation:

by calculating initially (R)_i) And finally (R)_f) And (5) further reducing the data. They are the average ratio of the sample point period during part or all of the pre-stimulation period and the stimulation period. The response to the stimulus p R is then calculated_f/R_i。

A control response is obtained by performing the assay in the presence of a compound having the desired property (positive control) and in the absence of a pharmacological agent (negative control). Responses to the negative control (N) and the positive control (P) were calculated as described above. Activity a of assay wells relative to positive and negative controls was defined as:

electrophysiological assay for NaV activity and inhibition of test compounds

The efficacy and selectivity of sodium channel blockers in dorsal root ganglion neurons was assessed using patch clamp electrophysiology. Rat neurons were isolated from dorsal root ganglia and maintained in culture for 2-10 days in the presence of NGF (50ng/ml) (medium consisting of Neurobasal a, supplemented with B27, glutamine and antibiotics). Small diameter neurons (nociceptors, 8-12 μm in diameter) were identified visually and probed with a fine tip glass electrode connected to an amplifier (Axon Instruments). Cells were maintained at-60 mV and IC50 for compounds was assessed using a "voltage clamp" mode. In addition, the efficacy of compounds in blocking the generation of action potentials in response to current injection was tested using a "current clamp" model. The results of these experiments help to determine the efficacy profile of the compounds.

Voltage clamp assay in DRG neurons

TTX-tolerant sodium currents from DRG somatic cells were recorded using whole-cell changes in patch clamp technique. Recordings were made at room temperature (. about.22 ℃ C.) using an Axomatch 200B amplifier (Axon Instruments) and a thick-walled borosilicate glass electrode (WPI; resistance 3-4 M.OMEGA.). After the whole cell construct was established, the pipette solution was allowed to equilibrate within the cells for approximately 15 minutes before starting the recording. The current was low pass filtered between 2-5kHz and sampled digitally at 10 kHz. The series resistance was compensated for 60-70% and monitored continuously throughout the experiment. The liquid junction potential (-7mV) between the intracellular pipette solution and the external recording solution was not included in the data analysis. The test solution was supplied to the cells using a gravity-driven rapid perfusion system (SF-77; Warner Instruments).

The dose-response relationship was determined in a voltage clamp mode by repeatedly depolarizing the cells from the experiment-specific holding potential to a test potential of +10mV once every 60 seconds. The retardation effect was allowed to reach a plateau before the next concentration tested was performed.

Solutions of

Intracellular solution (mM): Cs-F (130), NaCl (10), MgCl₂(1)，EGTA(1.5)，CaCl₂(0.1), HEPES (10), glucose (2), pH 7.42, 290 mOsm.

Extracellular solution (mM): NaCl (138), CaCl₂(1.26)，KCl(5.33)，KH₂PO₄(0.44)，MgCl₂(0.5)，MgSO₄(0.41)，NaHCO₃(4)，Na₂HPO₄(0.3), glucose (5.6), HEPES (10), CdCl₂(0.4)，NiCl₂(0.1)，TTX(0.25x10^-3)。

Current clamp assay for NaV channel inhibitory activity of compounds

Current clamps were applied to cells in a whole cell configuration using a Multiplane 700A amplifier (Axon Inst.). Fill to borosilicate pipette (4-5MOhm) (mM): 150 parts of potassium gluconate, 10 parts of NaCl, 0.1 part of EGTA, 10 parts of HEPES, 2 parts of MgCl₂(buffered to pH7.34 with KOH). Cells were soaked in (mM): 140NaCl, 3KCl, 1MgCl₂、1CaCl₂And 10 HEPES. Zeroing the pipette potential before the seal is formed; the liquid junction potential was not corrected during acquisition. The recording was performed at room temperature.

The exemplary compounds of table 1 herein are active against one or more sodium channels as determined using the assays described above.

The compounds of the invention have activity against NaV1.3 channels.

The activity against the NaV1.3 channel of selected compounds of the invention is shown in table 3 below. In table 3, the letter symbols have the following meanings:

"A" means < 2. mu.M; "B" means 2. mu.M-10. mu.M; "C" means 10. mu.M-20. mu.M; "D" means > 20. mu.M.

TABLE 3

The compounds of the invention have activity against the NaV1.7 channel.

The activity against the NaV1.7 channel of selected compounds of the invention is shown in table 4 below. In table 4, the letter symbols have the following meanings:

"A" means < 2. mu.M; "B" means 2. mu.M-10. mu.M; "C" means 10. mu.M-20. mu.M; "D" means > 20. mu.M.

TABLE 4

The compounds of the invention have activity against NaV1.8 channels.

The activity against NaV1.8 channel of selected compounds of the invention is shown in table 5 below. In table 5, the letter symbols have the following meanings:

"A" means < 2. mu.M; "B" means 2. mu.M-10. mu.M; "C" means 10. mu.M-20. mu.M; "D" means > 20. mu.M.

TABLE 5

All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the invention as defined by the appended claims.

Claims (20)

1. A compound of formula I':

or a pharmaceutically acceptable salt thereof, wherein:

ring B is a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein ring B is optionally substituted with up to x R³Substitution;

X¹、X²、X³and X⁴Each independently is nitrogen or C-R⁴Provided that X is¹、X²、X³And X⁴Is not nitrogen at the same time;

each R²Independently hydrogen, or C_1-6Aliphatic radical in which up to 2 carbon atoms, other than the atom bound to the nitrogen atom, are optionally O, S, NR^NOr C (O) instead;

x is 0 to 4;

R^Neach independently selected from hydrogen or C_1-6An aliphatic group optionally substituted with 1-3 independent substituents selected from the group consisting of: -R^JOxo, thio, -CO₂R^J、-OR^J、-N(R^J)₂、-SR^J、-NO₂Halogen, -CN, -C_1-4Haloalkyl, -C_1-4Haloalkoxy, -C (O) N (R)^J)₂、-NR^JC(O)R^J、-SO₂R^J、-SO₂N(R^J)₂、-NR^JSO₂R^J、-NR^JCON(R^J)₂、-NR^JCO₂R^J、-COR^J、-OCOR^J、-OCON(R^J)₂、-SOR^J、-NR^JSO₂N(R^J)₂、-COCOR^J、-COCH₂COR^J、-OP(O)(OR^J)₂、-P(O)(OR^J)₂、-PO(OR^J)(R^J)、-P(O)(R^J)₂or-OP (O) (R)^J)₂(ii) a Wherein

R^JIs hydrogen or unsubstituted C_1-6An aliphatic group;

R³and R⁴Each independently is Q-R^X；

Q is a bond or C_1-6An aliphatic chain in which up to 3 methylene units of Q are optionally and independently replaced by: -NH-, -NR-, -O-, -S-, -CO-, -C₂-、-OC(O)-、-C(O)CO-、-C(O)-、-C(S)-、-C(O)NH-、-C(O)NR-、-C(＝N-CN)-、-NHCO-、-NRCO-、-NHC(O)O-、-NRC(O)O-、-SO₂NH-、-SO₂NR-、-NHSO₂-、-NRSO₂-、-NHC(O)NH-、-NRC(O)NH-、-NHC(O)NR-、-NRC(O)NR、-OC(O)NH-、-OC(O)NR-、-NHSO₂NH-、-NRSO₂NH-、-NHSO₂NR-、-NRSO₂NR-, -SO-or-SO₂-; wherein

Q is optionally substituted with 1-3 independent R^QAnd (3) substitution:

R^Xeach independently selected from-R', halogen, -NO₂、-CN、-OR′、-SR′、-N(R′)₂、-NR′C(O)R′、-NR′C(O)N(R′)₂、-NR′CO₂R′、-C(O)R′、-CO₂R′、-OC(O)R′、-C(O)N(R′)₂、-OC(O)N(R′)₂、-SOR′、-SO₂R′、-SO₂N(R′)₂、-NR′SO₂R′、-NR′SO₂N(R′)₂、-C(O)C(O)R′、-C(O)CH₂C(O)R′、-OP(O)(OR′)₂、-P(O)(OR′)₂、-PO(OR′)(R′)、-P(O)(R′)₂or-OP (O) (R')₂；

Each R is independently selected from hydrogen or C_1-6An aliphatic group optionally substituted with 1-3 independent substituents selected from the group consisting of: -R^T、-T-Ar¹Halogen, oxo, thio, -OR^T、-SR^T、-N(R^T)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R^T、-COR^T、-CON(R^T)₂、-OCOR^T、-NR^TCOR^T、-SO₂R^T、-SO₂N(R^T)₂or-NR^TSO₂R^T(ii) a Wherein

Each R^TIndependently is hydrogen or unsubstituted C_1-6An aliphatic group; or

Any two R on the same substituent or different substituents^TThe groups together with the atoms to which each group is attached optionally form a 3-8 membered saturated or partially unsaturated monocyclic, or 5-6 membered monocyclic aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein said monocyclic ring is optionally substituted with 1-3 independent substituents selected from the group consisting of: -R^R、-T-Ar¹Halogen, oxo, thio, -OR^R、-SR^R、-N(R^R)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R^R、-COR^R、-CON(R^R)₂、-OCOR^R、-NR^RCOR^R、-SO₂R^R、-SO₂N(R^R)₂or-NR^RSO₂R^R(ii) a Wherein

Each R^RIndependently is hydrogen or unsubstituted C_1-6An aliphatic group;

t is (CH)₂)_w；

w is 0 to 2;

Ar¹selected from a 3-8 membered saturated or partially unsaturated ring, a 5-6 membered aromatic ring, a 3-7 membered heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein

Ar¹Optionally substituted with 1-3 independent substituents: -R^WOxo, thio, -CO₂R^W、-OR^W、-N(R^W)₂、-SR^W、-NO₂Halogen, -CN, -C_1-4Haloalkyl, -C_1-4Haloalkoxy, -C (O) N (R)^W)₂、-NR^WC(O)R^W、-SO₂R^W、-SO₂N(R^W)₂、-NR^WSO₂R^W、-NR^WCON(R^W)₂、-NR^WCO₂R^W、-COR^W、-OCOR^W、-OCON(R^W)₂、-SOR^W、-NR^WSO₂N(R^W)₂、-COCOR^W、-COCH₂COR^W、-OP(O)(OR^W)₂、-P(O)(OR^W)₂、-PO(OR^W)(R^W)、-P(O)(R^W)₂or-OP (O) (R)^W)₂(ii) a Wherein

R^WIs hydrogen or unsubstituted C_1-6An aliphatic group;

R^Qselected from halogen, -R^S、-N(R^S)₂、-SR^S、-OR^S、C_3-10Alicyclic group, C_6-10Aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, oxo, thioxo, -C_1-4Haloalkoxy, -C_1-4Haloalkyl, -NO₂、-CN、-CF₃、-OCF₃、-CO₂R^S、-COR^S、-OC(O)R^Sor-NR^SC(O)R^S(ii) a Wherein

R^SIs hydrogen or unsubstituted C_1-6An aliphatic group; or

Any two R on the same substituent or different substituents^QOr two R^SA group, or R^QGroup and R^SAny combination of groups, together with one or more atoms to which each group is attached, optionally form a 3-8 membered saturated or partially unsaturated monocyclic, or 5-6 membered monocyclic aromatic ring; each ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein any of said monocyclic rings is optionally substituted with 1-3 independent substituents selected from the group consisting of: r⁰Halogen, oxo, thio, -OR⁰、-SR⁰、-N(R⁰)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R⁰、-COR⁰、-CON(R⁰)₂、-OCOR⁰、-NR⁰COR⁰、-SO₂R⁰、-SO₂N(R⁰)₂or-NR⁰SO₂R⁰(ii) a Wherein

R⁰Is hydrogen or unsubstituted C_1-6An aliphatic group;

r' is independently selected from hydrogen or C_1-8Aliphatic radical, C_6-10Aryl, heteroaromatic ring having 5 to 10 ring atoms, or heterocyclic ring having 3 to 10 ring atoms, or wherein R and R 'are taken together with one or more atoms to which they are attached, or 2R' are taken together with atoms to which they are attachedThe atoms attached together form a 5-8 membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein said C_1-8Aliphatic radical, C_6-10The aryl, heteroaryl ring or heterocycle is optionally substituted with 1-3 independent substituents selected from the group consisting of: r^IHalogen, oxo, thio, -OR^I、-SR^I、-N(R^I)₂、-NO₂、-C_1-4Haloalkyl, -C_1-4Haloalkoxy, -CN, -CO₂R^I、-COR^I、-CONHR^I、-OCOR^I、-NR^ICOR^I、-SO₂R^I、-SO₂N(R^I)₂or-NR^ISO₂R^I(ii) a Wherein

R^IIs hydrogen or unsubstituted C_1-6An aliphatic group.

2. The compound of claim 1, wherein ring B is an optionally substituted 6-membered heteroaryl ring.

3. The compound of claim 2, wherein ring B is selected from:

4. the compound of claim 1, wherein ring B is an optionally substituted 5-membered heteroaromatic ring.

5. The compound of claim 4, wherein ring B is selected from:

6. the compound of claim 5, wherein ring B is selected from:

7. the compound of claim 1, wherein x is 1-3.

8. The compound of claim 7 wherein x is 1-3 and each R³Independently selected from hydrogen, halogen, CN, CF₃、NO₂Or optionally substituted groups selected from: c_1-6Aliphatic radical, C_1-6Alicyclic group, C_6-10Aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, arylalkyl, -N (R')₂、-CH₂N(R′)₂、-OR′、-CH₂OR′、-SR′、-CH₂SR′、-C(O)R′、-COOR′、-NRCOR′、-CON(R′)₂、-S(O)₂R', or-S (O)₂N(R′)₂。

9. The compound of claim 8 wherein x is 1-2 and each R³Is methyl, ethyl, propyl, isopropyl, tert-butyl, sec-butyl, or optionally substituted group selected from: c_1-6Aliphatic radical, C_6-10Aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl or aralkyl.

10. The compound of claim 1, wherein the group

11. The compound of claim 1, wherein each R⁴Is hydrogen.

12. The compound of claim 1Wherein each R⁴When present, is independently selected from hydrogen, halogen, CN, NO₂Or optionally substituted groups selected from: c_1-6Aliphatic, aryl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, aralkyl, -N (R')₂、-CH₂N(R′)₂、-OR′、-CH₂OR′、-SR′、-CH₂SR′、-C(O)R′、-COOR′、-NR′COR′、-CON(R′)₂or-S (O)₂N(R′)₂。

13. The compound of claim 1 wherein at SO₂N(R²)₂In two, R²Are all hydrogen.

14. A compound selected from table 1.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

16. The pharmaceutical composition of claim 15, further comprising an additional therapeutic agent.

17. A method of treating or lessening the severity of the following diseases in a subject: acute, chronic, neuropathic, or inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy or epilepsy disorders, neurodegenerative diseases, psychiatric disorders such as anxiety and depression, bipolar disorders, myotonia, arrhythmia, movement disorders, neuroendocrine diseases, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, penetrating pain, post-operative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress or exercise-induced angina, palpitation, hypertension, migraine or abnormal gastrointestinal activity,

the method comprising administering to said subject in need thereof an effective amount of a compound of claim 1 or a pharmaceutically acceptable composition comprising the compound.

18. The method of claim 17, wherein the method is used to treat or reduce the severity of: acute, chronic, neuropathic, or inflammatory pain.

19. The method of claim 17, wherein the method is used to treat or reduce the severity of: radicular pain, sciatica, back pain, headache, neck pain, intractable pain, acute pain, post-operative pain, back pain, tinnitus, or cancer pain.

20. The method of claim 17, wherein the method is used to treat or reduce the severity of: femoral cancer pain; non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis; spinal stenosis; neuropathic lumbago; neuropathic lumbago; myofascial pain syndrome; fibromyalgia; temporomandibular joint pain; chronic visceral pain, including abdominal pain; pain in the pancreas; IBS pain; chronic and acute headache; migraine headache; tension headaches, including cluster headaches; chronic and acute neuropathic pain, including post-herpetic neuralgia; diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia; charcot-horse-charcot-type neuropathy; hereditary sensory neuropathy; peripheral nerve damage; painful neuroma; ectopic proximal or distal discharges; a radiculopathy; chemotherapy-induced neuropathic pain; radiotherapy-induced neuropathic pain; pain after mastectomy; central pain; pain from spinal cord injury; pain following stroke; thalalgia; complex regional pain syndrome; phantom pain; intractable pain; acute pain, acute post-operative pain; acute musculoskeletal pain; joint pain; mechanical low back pain; neck pain; tendonitis; injury/athletic pain; acute visceral pain, including abdominal pain; pyelonephritis; appendicitis; cholecystitis (cholecystitis); ileus; hernia, etc.; chest pain, including cardiac pain; pelvic pain, renal colic, acute obstetrical pain, including childbirth pain; cesarean labor pain; acute inflammatory pain, burn pain and trauma pain; acute intermittent pain, including endometriosis; acute herpes zoster pain; sickle cell anemia; acute pancreatitis; breakthrough pain; or oral and facial pain, including sinusitis pain, dental pain; multiple Sclerosis (MS) pain; pain in depression; leprosy pain; becker's disease pain; painful obesity; pain from phlebitis; pain from Guillain-Barre disease; lower limb pain and toe movement; haglund syndrome; erythematous limb pain; pain from fabry disease; bladder and genitourinary disorders, including urinary incontinence; overactive bladder; painful bladder syndrome; interstitial Cystitis (IC); or prostatitis; complex regional pain syndrome of type I and type II (CRPS); or pain induced by angina.